Catalytic Regio- and Stereoselective

Reactions for the Synthesis of Allylic

and Homoallylic Compounds

Rauful Alam

ii

copy RAUFUL ALAM Stockholm 2015

Cover picture Rauful Alam

ISBN 978-91-7649-282-6

Printed in Sweden by E-print AB 2015

Distributor Department of Organic Chemistry Stockholm University

iii

আমমাrsquoকেmdashকে আমাকে দrsquoটি টিনন অনধোর কেকে আক া কদটিকেকে

এবং আববাrsquoকেmdashধরব োো হকে আকেন টেটন

To my parents

iv

v

Abstract

This thesis is focused on two main areas of organic synthesis palladium-

catalyzed functionalization of alkenes and allylic alcohols as well as devel-

opment of new allylboration reactions

We have developed a palladium-catalyzed selective allylic trifluoroace-

toxylation reaction based on CminusH functionalization Allylic trifluoroacetates

were synthesized from functionalized olefins under oxidative conditions

The reactions proceed under mild conditions with a high level of diastereose-

lectivity Mechanistic studies of the allylic CminusH trifluoroacetoxylation

indicate that the reaction proceeds via (η3-allyl)palladium(IV) intermediate

Palladium-catalyzed regio- and stereoselective synthesis of allylboronic

acids from allylic alcohols has been demonstrated Diboronic acid B2(OH)4

was used as the boron source in this process

The reactivity of the allylboronic acids were studied in three types of

allylboration reactions allylboration of ketones imines and acyl hydrazones

All three processes are conducted under mild conditions without any

additives The reactions proceeded with remarkably high regio- and stereose-

lectivity

An asymmetric version of the allylboration of ketones was also devel-

oped In this process chiral BINOL derivatives were used as catalysts The

reaction using γ-disubstituted allylboronic acids and various aromatic and

aliphatic ketones afforded homoallylic alcohols bearing two adjacent quater-

nary stereocenters with excellent regio- diastereo- and enantioselectivity (up

to 973 er) in high yield The stereoselectivity in the allylboration reactions

could be rationalized on the basis of the Zimmerman-Traxler TS model

vi

vii

List of Publications

This thesis is based on a licentiate thesis by Rauful Alam entitled ldquoPalladi-

um-catalyzed Allylic CminusH and CminusOH Functionalization Reactions of the

Obtained Allylboronic Acidsrdquo and the following papers referred to in text

by their Roman numerals I-VI Reprints were made with the kind permission

from the publishers (Appendix A)

I Stereoselective Intermolecular Allylic C-H Trifluoroacetoxylation

of Functionalized Alkenes

Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

II Palladium-Catalyzed Synthesis and Isolation of Functionalized

Allylboronic Acids Facile Direct Allylboration of Ketones Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

III Selective Formation of Adjacent Stereocenters by Allylboration of

Ketones under Mild Neutral Conditions Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

IV Synthesis of Adjacent Quaternary Stereocenters by Catalytic

Asymmetric Allylboration

Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

V Stereoselective Allylboration of Imines and Indoles under Mild

Conditions An in situ EZ Isomerization of Imines by Allylborox-

ines Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

VI Stereocontrol in Synthesis of Homoallylic Amines Syn Selective

Direct Allylation of Hydrazones with Allylboronic Acids Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

viii

Contents

Abstract v

List of Publications vii

Contents viii

Abbreviations xi

1 Introduction 1

11 Palladium-catalyzed allylic CminusH acetoxylation 1

12 Synthesis of allylboronates 2

13 Application of allylboronates in synthesis 4

131 Stereoselective allylation of carbonyl compounds 4

132 Enantioselective allylation of carbonyl compounds 5

133 Stereoselective allylation of imines 9

2 Pd-catalyzed stereoselective allylic CminusH trifluoroacetoxylation (Paper I) 11

21 Development of selective intermolecular allylic CminusH

trifluoroacetoxylationhelliphelliphelliphellip 12

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation 15

23 Conclusions for the allylic CminusH trifluoroacetoxylation 17

3 Pd-catalyzed synthesis and isolation of allylboronic acids (Paper II) 18

31 Development of new synthetic methods for the synthesis and isolation of

allylboronic acids 18

311 Diboronic acid B2(OH)4 as boron source 19

312 Synthesis of allylboronic acids and their isolation 20

32 Characterization of allylboroxine 22

33 Proposed mechanism for the allylic CminusOH borylation 24

34 Conclusions for the allylic CminusOH borylation 25

4 Allylboration of carbonyl compounds using allylboronic acids (Paper II-III) 26

41 Allylation of ketones by allylboronic acids 26

42 Stereoselectivity of α-hydroxy acids 31

43 Conclusions for allylboration of carbonyl compounds 32

ix

5 Synthesis of adjacent quaternary stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV) 33

51 Method development for the asymmetric allylboration of ketones helliphellip33

52 Stereocontrol in the asymmetric allylboration of ketone 35

53 Catalytic enantioselective allylboration of ketones 36

54 Proposed mechanism for the enantioselectivity of the allylboration of

ketones with allylboronic acids 38

541 Proposed models for enantioselectivity 40

542 Proposed catalytic cycle 41

55 Conclusions for the catalytic asymmetric allylboration 42

6 Allylboration of imines indoles and hydrazones (Paper V-VI) 43

61 Allylation of imines with allylboronic acids 43

62 Allylation of indoles with allylboronic acids 46

63 Allylation of acyl hydrazones with allylboronic acids 48

64 Mechanistic study and proposal for the allylation of aldimines 50

65 Proposed mechanism for the allylboration of hydrazones 52

66 Proposed mechanism for the allylboration of indoles 54

67 Conclusions for the allylboration of imines indoles and hydrazones 55

7 Concluding remarks 56

8 Acknowledgements 57

9 Summary in Swedish 58

10 Appendix A 59

11 References 60

x

xi

Abbreviations

Abbreviations are used in agreement with standards of the subject1 Addi-

tional non-standard or unconventional abbreviations that appear in this thesis

are listed below

B2pin2 bis(pinacolato)diboron

BINOL 11-bi-2-naphthol

Bpin pinacolato boron

BQ 14-benzoquinone

dba dibenzylideneacetone

DFT density functional theory

DMC dimethyl carbonate

dr diastereomeric ratio

er enantiomeric ratio

LA Lewis acid

L ligand (neutral)

L chiral ligand

MS molecular sieves

NOE nuclear Overhauser effect

PIFA phenyliodine bis(trifluoroacetate)

PIDA phenyliodonium diacetate

TFA trifluoroacetate

TS transition state

rt room temperature

X ligand (charged)

1

1 Introduction

The development of highly selective transformations is of fundamental

importance in modern organic chemistry Transition metal-catalysis is one of

the useful synthetic approaches to achieve this goal2 The allylation reaction

using allylboron reagents and other allyl sources is also an important ap-

proach to develop selective syntheses3

11 Palladium-catalyzed allylic CminusH acetoxylation

Transition metal-catalyzed substitution of allylic acetates and their ana-

logs is one of the most utilized and studied reactions4 An important method

to synthesize allylic acetates is Pd-catalyzed allylic CminusH functionalization5

Pioneering works by McMurry and Kocovsky6 and Aringkermark

7 have shown

that Pd(II)-catalyzed allylic acetoxylation of cyclic and acyclic olefins can

be achieved in the presence of acetic acid and benzoquinone (BQ) as oxidant

(Scheme 1) Mechanistic investigations by Baumlckvall8 and co-workers

indicated that a (π-allyl)palladium(II) intermediates are involved in the

process and that BQ serves as both oxidant and activator ligand in the

CminusOAc bond formation process

Scheme 1 Pd-catalyzed allylic CminusH acetoxylation reaction

7a

Recently the White9 and the Stahl

10 group independently reported new

methods for CminusH acetoxylation reactions using palladium catalysis The

latter group used O2 as an oxidant instead of BQ According to the mechanis-

tic studies by these authors the CminusH acetoxylation process take place via

Pd0 and Pd

II catalytic intermediates

Hypervalent iodine reagents were also employed as the principal compo-

nent in the allylic CminusH oxidation reactions5 11

For example Szaboacute and

co-workers11b

have reported the allylic CminusH acyloxylation reaction with

PhI(OAc)2 (2a) as the oxidant and source of OAc (Scheme 2) The use of a

2

palladium catalysts and hypervalent iodine reagents allowed an easy access

to allylic acetoxy and benzoyloxy compounds Based on the mechanistic

studies a PdIIPd

IV catalytic cycle was proposed when PhI(OAc)2 was used

as the oxidant

Scheme 2 Pd-catalyzed CminusH acetoxylation reaction reported by Szaboacute and co-

workers11b

In spite of the wide application of allylic CminusH acyloxylation reactions in

organic synthesis the stereoselective transformations of substituted cyclic

alkenes are limited Particularly the intermolecular diastereoselective CminusH

acyloxylation is still a challenge A new synthetic process for such a reaction

is presented in Chapter 2

12 Synthesis of allylboronates

Allylboronates are efficient reagents for regio- and stereoselective allyla-

tion of carbonyl compounds and some related functionalities3 12

Due to the

importance of allylboronates in synthetic organic chemistry there has been a

large interest in the development of new methods for the synthesis of these

reagents The classical synthetic procedures involve application of allyl-

Grignard and allyl-Li reagents13

However these methods have a limited

synthetic scope because of problems with the regioselective formation of the

allylboronates Palladium-catalyzed methods based on the substitution of allylic alcohol

derivatives have proven to be a versatile and relatively simple method to

obtain allylboronates The first process was reported by Miyaura and

co-workers14

(Scheme 3) In this process B2pin2 was used as the boron

source Although the regioselectivity of the reaction is excellent a drawback

of this process is the formation of varying amounts of homocoupling prod-

ucts

Scheme 3 Pd-catalyzed borylation of allylacetates

14

The Szaboacute group15

has expanded the substrate scope to include allylic

alcohols instead of allylic acetates (Scheme 4) It was also shown that

3

certain Pd(II) pincer complexes are more efficient than Pd(dba)2 In depth

mechanistic studies revealed that catalytic amounts of Lewis or Broslashnsted

acids are required in the reaction to activate the allylic alcohols for Pd-

catalyzed substitution16

The reaction is substantially accelerated in the pres-

ence of MeOH or other protic co-solvents

Scheme 4 Pd-catalyzed borylation of allylic alcohols

15c 15d

The Szaboacute group also developed palladium-catalyzed allylic C-H boryla-

tion methods17

These processes allowed for the synthesis of allylboronates

from readily available alkenes under oxidative conditions using BQ (1) or

the hypervalent iodonium salt

Ito Sawamura and their co-workers reported the regio- and stereoselec-

tive synthesis of allylboronates by Cu-catalyzed substitution of allyl

carbonates18

This method can also be extended to asymmetric catalysis for

the synthesis of enantioenriched allylboronates (Scheme 5)19

Scheme 5 Cu-catalyzed asymmetric borylation of allylcarbonates

19

Enantioselective synthesis of α-substituted allylboronates has been

reported by Hall and co-workers (Scheme 6)20

This method is based on

copper-catalyzed substitution of allylhalide substrates The chiral

allylboronates generated in this reaction were used for further transformation

without isolation

Scheme 6 Cu-catalyzed borylation reported by Hall and co-workers

20

Related Cu-catalyzed asymmetric synthesis of allylboronates have also

been independently reported by the groups of Hoveyda21

and McQuade22

Nickel-catalyzed stereospecific borylation of allylic acetates was developed

by Morken and co-workers23

The reaction is highly selective for the termi-

4

nal allylboronates (Scheme 7) The Morken group also developed palladi-

um-catalyzed enantioselective borylation methods for the synthesis of al-

lylboronates24

Scheme 7 Ni-catalyzed selective borylation of allylic acetates

23

Very recently Aggarwal and co-workers have reported a new method for

the preparation of enantioenriched allylboronates25

This so called ldquolithia-

tion-borylation methodrdquo involves homologation of vinyl boronates using

alkyl carbamates and butyllithium (BuLi) in the presence of (+)-sparteine

(Scheme 8)

Scheme 8 Synthesis of allylboronates by lithiation-borylation method

25b

As shown above synthesis of allylboron reagents has attracted large in-

terest in modern organic chemistry As a contribution to this field we devel-

oped a new method for the synthesis and isolation of allylboronic acids

which is presented in Chapter 3

13 Application of allylboronates in synthesis

Allylboronate reagents have been extensively used to synthesize numerous precursors for natural products and bioactive molecules

26

Addition of allylboronates to carbonyl and imine electrophiles is a well studied and documented reactions in synthetic organic chemistry

131 Stereoselective allylation of carbonyl compounds

Allylboration reactions of aldehydes have been widely applied for the ste-

reoselective synthesis of homoallylic alcohols3 After the discovery by Bub-

nov27

the reaction was further developed by Hoffmann28

Brown29

Roush30

and others Hoffmann and Brown carried out in depth mechanistic studies

which also explained the stereochemistry of the reaction Hoffman postulat-

ed that the reaction between allylboronates and aldehydes proceeds via a six-

5

membered cyclic TS similar to the Zimmerman-Traxler31

model (Scheme

9)28a 32

The high diastereoselectivity of the allylboration reaction is attributed to

an internal Lewis acid activation of the carbonyl functionality by the empty

p-orbital of boron

Scheme 9 Zimmerman-Traxler model to describe stereochemistry of allylboration

reaction

The addition of Lewis or Broslashnsted acids may accelerate the allylboration

of carbonyl compounds33

Hall and co-workers proposed that Lewis acids

coordinate to the lone pair of the boronate oxygen which renders the boron

atom more electron deficient (Scheme 10)33b 34

This mechanism for LA

and Broslashnsted acid activation was also confirmed by the DFT studies of

Houk and co-workers35

Scheme 10 Possible modes of Lewis acid activation for the allylboration

Allylboronates can also react with ketones yielding tertiary homoallylic

alcohols However the addition of allylboronates to ketones is much slower

than similar reactions with aldehydes Thus the selective allylation of

ketones with allylboronates often requires the use of catalysts36

In addition

most of the present methods for allylboration of ketones are limited to the

use of unsubstituted (parent) allylboronates or crotylboronates

132 Enantioselective allylation of carbonyl compounds

There are basically two main approaches for the asymmetric allylboration

of carbonyl compounds The first approach is the application of enantioen-

riched allylboronates performing chirality transfer and the second one is

6

asymmetric induction by using chiral catalyst One of the first asymmetric

allylboration reactions was reported by Roush and co-workers 13b 37

These

authors employed chiral auxiliaries attached to the boron atom (Scheme 11)

Diisopropyl tartrate (DIPT) proved to be a very efficient chiral auxiliary to

induce enantioselectivity

Scheme 11 Asymmetric allylation of aldehydes using chiral allylboronate

13b

A similar approach was reported by Soderquist and co-workers38

for the

asymmetric allylboration of aldehyde and ketones A bicyclic chiral auxilia-

ry on the boron atom was employed for highly diastereo- and enantioselec-

tive allylboration (Scheme 12)

Scheme 12 Diastereo-and enantioselective allylboration by chiral allylborane

38a

Enantiomerically pure TADDOL based allylboronates were developed by

Pietruszka and co-workers39

These reagents were used for chirality transfer

in allylboration of aldehydes (Scheme 13) The chiral auxiliary can be

recovered after the allylation by reduction with LiAlH4

Scheme 13 Asymmetric allylation of aldehyde using enantiopure allylboronate

39

Metal-catalyzed asymmetric synthesis of heterocyclic allylboronates was

described by Hall and co-workers40

These allylboronates were used in situ

for allylboration of aldehydes The key-step in synthesis of mefloquine was

performed using this method (Scheme 14)

7

Scheme 14 Asymmetric allylboration by cyclic allylboronates

40

Very recently Aggarwal and co-workers25b 41

reported an efficient

allylboration method using α-substituted enantioenriched allylboronates (see

also Scheme 8) The method is highly diastereo- and enantioselective In

addition the procedure is suitable for the synthesis of homoallylic alcohols

with two adjacent quaternary stereocenters (Scheme 15)

Scheme 15 Asymmetric allylation of ketone by α-substituted chiral allylboronate

25b

An alternative approach for the asymmetric allylboration of carbonyl

compounds involves the application of chiral catalysts Both Lewis and

Broslashnsted acids have been used for the asymmetric allylboration reactions

The first catalytic enantioselective allylboration reaction was reported by

Miyaura and co-workers (Scheme 16)33c

This reaction proceeded with a

high regio- and diastereoselectivity but the enantioselectivity was relatively

low

Scheme 16 Catalytic asymmetric allylboration of aldehyde

33c

Hall and co-workers42

reported a Sn-catalyzed asymmetric allylboration

reaction using allyl-Bpin as the allyl source A chiral diol was used as a lig-

and in this process which was supposed to coordinate to SnCl4 (Scheme 17)

8

Scheme 17 Tin-catalyzed asymmetric allylboration of aldehyde

42a

Asymmetric allylation of ketones was reported using chiral allylboronate

derived from BINOL compounds Chong and co-workers described the al-

lylation of ketones using 33-(CF3)2-BINOL boronate 3a (Scheme 18)43

The

reaction gave homoallylic alcohol product with a high level of enantioselec-

tivity

Scheme 18 Asymmetric allylation of ketone using BINOL-boronate

43

Catalytic methods have also been described to control both diastereo- and

enantioselectivity in the allylboration of ketones44

The first catalytic

enantioselective allylboration of ketones was developed by Shibasaki and

co-workers45

Broslashnsted acid such as BINOL derivatives44 46

was found to be

very efficient in the asymmetric allylboration reactions Schaus and

co-workers44

reported a method for asymmetric allylation of ketones using

isopropoxyboronate and catalytic amounts of Br2-BINOL 4a (Scheme 19)

Scheme 19 Catalytic asymmetric allylboration of ketone using Br2-BINOL

44a

These authors proposed a Zimmerman-Traxler type transition state to

rationalize the enantioselectivity in this reaction It has been also pointed out

that the substituent in BINOL (eg Br or CF3) has an important role for the

enantioselectivity of these reactions

Catalytic synthesis of homoallylic alcohols containing adjacent quater-

nary stereocenters has been a great challenge in synthetic organic chemistry

A new synthetic method for such reaction is presented in Section 52

9

133 Stereoselective allylation of imines

Homoallylic amine motifs occur in many natural products and biological-

ly relevant compounds47

One of the most common strategies for homoallylic

amine synthesis is the addition of allyl-metal reagents to imines48

The use of

allylboronate compounds for these reactions has emerged as an important

synthetic approach47

Allylboronates have a low toxicity high functional

group tolerance and the allylation of imines occurs with a high level of

selectivity

Stereoselective allylation of aldimines can be performed by

allylboronates in the presence of Lewis acid catalysts Batey and

co-workers49

reported the allylboration of N-toluenesulfonylimines using

crotyltrifluroboronate and BF3OEt2 (Scheme 20) The allylation was

proposed to proceed via the allyl-BF2 species which is generated from

allyl-BF3K

Scheme 20 Stereoselective allylation of imine by allyltrifluoroborate

49

Kobayashi and co-workers50

reported a three-component diastereoselec-

tive allylation reaction to synthesize homoallylic primary amines (Scheme

21) In addition several useful methods for asymmetric allylboration of

imines25b 51

using allylboronates can also be found in literature

Scheme 21 Synthesis of homoallylic amine using multicomponent method

50

Allylboration of acylhydrazones have also proven to be a very useful

reaction for the synthesis of homoallylic amine derivatives However the

allylation of acylhydrazones by allylboronates requires the application of

metal catalysts52

An indium-catalyzed reaction for the allylation of N-

acylhydrazone was reported by Kobayashi and co-workers (Scheme 22)52a

It

has been proposed that indium undergoes a transmetallation with allyl-Bpin

to form an active allyl-indium species which then added to the hydrazone

10

Scheme 22 Indium-catalyzed allylation of acylhydrazone

52a

We have developed a stereoselective method for allylation of imines and

acylhydrazones using allylboronic acids These results are summarized in

Chapter 6

11

2 Pd-catalyzed stereoselective allylic CminusH

trifluoroacetoxylation (Paper I)

As mentioned in the introduction transition metal-catalyzed CminusH bond activation methods have attracted increasing interest in organic synthesis

53

Using these methods multistep synthesis for prefunctionalization of the or-ganic substrates is not necessary In addition the waste production of the reaction can be reduced as the new functional group can be installed by re-placement of hydrogen

54 Palladium-catalyzed allylic CminusH bond activation is

one of the oldest and most versatile CminusH functionalization method (Section 11)

55 In this reaction (as in CminusH activation based processes in general) the

greatest challenge is the control of the regio- and stereoselectivity of the process

Stereodefined allylic acetates are very important precursors for regio- and stereoselective palladium-catalyzed allylic substitution reactions

56 Although

many regioselective allylic CminusH functionalization methods have been re-ported there are few reports on stereoselective allylic CminusH acetoxylation

7a

Most of these studies are intramolecular CminusH acyloxylation reactions For example a stereoselective allylic CminusH acetoxylation method has been re-ported by White and co-workers (Scheme 23) Intramolecular selectivity control allowed macrocyclization

57 and straightforward synthesis of anti-14-

dioxan-2-ones58

from simple olefins using Pd(II)sulfoxide catalysis Baumlck-vall and co-workers

59 have also developed several methods for the synthesis

of allylacetoxy compounds based on palladium-catalyzed intramolecular oxidative carbocyclization

Scheme 23 Stereoselective intramolecular CminusH oxidation reported by White and

co-workers58

12

21 Development of selective intermolecular allylic CminusH trifluoroacetoxylation

As our group previously developed a useful allylic CminusH acetoxylation

method based on using PhI(OAc)2 (2a) (see Section 11) as oxidant and ace-

tate source we envisioned that PhI(OCOCF3)2 (2b) can also be used in this

type of reaction to introduce a trifluoroacetate group at the allylic position of

alkenes Allylic trifluoroacetates are more reactive than allylic acetates in

transition metal-catalyzed substitutions60

and therefore an easy access to

these compounds is desirable As far as we know selective allylic CminusH tri-

fluoroacetoxylation has not been reported in the literature

In the early stage of development and optimization we employed car-

boxylated alkene 6a as our model substrate as it gave a high yield and ex-

hibited high selectivity in the Pd-catalyzed CminusH acetoxylation with 2a11b

However PhI(OCOCF3)2 (2b) is most likely a stronger oxidant than

PhI(OAc)2 (2a) and therefore we could not use oxidation sensitive solvents

such as THF or DMSO In addition the conjugated acid of the trifluoroace-

tate ion (the nucleophile) is a strong acid and therefore trifluoroacetic acid

could not be used as the solvent either After short optimization we have

found that dimethyl carbonate (DMC) is an excellent solvent for all reaction

components and it is not oxidized by PIFA We have found that the isolated

yields are higher when LiOCOCF3 is used as additive Under these condi-

tions the reaction could be performed with various functionalized alkenes

(Table 1)

13

Table 1 Pd-catalyzed allylic CminusH trifluoroacetoxylation of acyclic olefinsa

Both Pd(OAc)2 (5b) and Pd(OCOCF3)2 (5c) were equally efficient as cat-

alyst in the reaction So we decided to use 5b in the present synthetic method

as it is less expensive than 5c Not only terminal (6a) but internal alkenes

6b-c could also be used for trifluoroacetoxylation with high selectivity Oth-

er alkenes with electron withdrawing substituents such as 6d-e could also be

smoothly trifluoroacetoxylated Substrates without electron-withdrawing

groups gave intractable mixtures of trifluoroacetoxylated products For com-

pounds with long alkyl chain oxidation of the double bond occurred while in

the case of electron donating substituents mainly oxidation of the double

bond occurred together with other processes

14

Table 2 Stereoselective allylic CminusH trifluoroacetoxylation of cyclic alkenesa

Not only acyclic alkenes but cyclic alkenes could also be employed for

the trifluoroacetoxylation reaction Monosubstituted cyclic alkenes reacted

with a remarkably high selectivity (Table 2) The reaction conditions were

very similar to the trifluoroacetoxylation of acyclic substrates (Table 1) but

in order to get this high stereoselectivity the reactions had to be conducted

at 0 degC This is below the freezing point of DMC therefore the reaction me-

dium was diluted with DCM to avoid freezing of the reaction mixture The

yields with LiOCOCF3 were as high as in its absence therefore we did not

use this additive in the trifluoroacetoxylation of cyclic substrates

Considering the number of possible regio- and stereoisomers a mixture

of six allylic trifluoroacetate products could be expected Yet in most cases

we obtained a single diastereomer with very high regioselectivity (Table 2

entries 1-2 and 4-5) The major regioisomer in all cases was the 14-

substituted product (7f-j) with anti diastereoselectivity and the minor prod-

uct is the regioisomer of the same diastereomer The stereochemistry of the

major isomers was assigned based on NOE experiments

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

1 The ACS Style Guide 3rd ed Oxford University Press New York 2006

2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

ii

copy RAUFUL ALAM Stockholm 2015

Cover picture Rauful Alam

ISBN 978-91-7649-282-6

Printed in Sweden by E-print AB 2015

Distributor Department of Organic Chemistry Stockholm University

iii

আমমাrsquoকেmdashকে আমাকে দrsquoটি টিনন অনধোর কেকে আক া কদটিকেকে

এবং আববাrsquoকেmdashধরব োো হকে আকেন টেটন

To my parents

iv

v

Abstract

This thesis is focused on two main areas of organic synthesis palladium-

catalyzed functionalization of alkenes and allylic alcohols as well as devel-

opment of new allylboration reactions

We have developed a palladium-catalyzed selective allylic trifluoroace-

toxylation reaction based on CminusH functionalization Allylic trifluoroacetates

were synthesized from functionalized olefins under oxidative conditions

The reactions proceed under mild conditions with a high level of diastereose-

lectivity Mechanistic studies of the allylic CminusH trifluoroacetoxylation

indicate that the reaction proceeds via (η3-allyl)palladium(IV) intermediate

Palladium-catalyzed regio- and stereoselective synthesis of allylboronic

acids from allylic alcohols has been demonstrated Diboronic acid B2(OH)4

was used as the boron source in this process

The reactivity of the allylboronic acids were studied in three types of

allylboration reactions allylboration of ketones imines and acyl hydrazones

All three processes are conducted under mild conditions without any

additives The reactions proceeded with remarkably high regio- and stereose-

lectivity

An asymmetric version of the allylboration of ketones was also devel-

oped In this process chiral BINOL derivatives were used as catalysts The

reaction using γ-disubstituted allylboronic acids and various aromatic and

aliphatic ketones afforded homoallylic alcohols bearing two adjacent quater-

nary stereocenters with excellent regio- diastereo- and enantioselectivity (up

to 973 er) in high yield The stereoselectivity in the allylboration reactions

could be rationalized on the basis of the Zimmerman-Traxler TS model

vi

vii

List of Publications

This thesis is based on a licentiate thesis by Rauful Alam entitled ldquoPalladi-

um-catalyzed Allylic CminusH and CminusOH Functionalization Reactions of the

Obtained Allylboronic Acidsrdquo and the following papers referred to in text

by their Roman numerals I-VI Reprints were made with the kind permission

from the publishers (Appendix A)

I Stereoselective Intermolecular Allylic C-H Trifluoroacetoxylation

of Functionalized Alkenes

Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

II Palladium-Catalyzed Synthesis and Isolation of Functionalized

Allylboronic Acids Facile Direct Allylboration of Ketones Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

III Selective Formation of Adjacent Stereocenters by Allylboration of

Ketones under Mild Neutral Conditions Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

IV Synthesis of Adjacent Quaternary Stereocenters by Catalytic

Asymmetric Allylboration

Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

V Stereoselective Allylboration of Imines and Indoles under Mild

Conditions An in situ EZ Isomerization of Imines by Allylborox-

ines Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

VI Stereocontrol in Synthesis of Homoallylic Amines Syn Selective

Direct Allylation of Hydrazones with Allylboronic Acids Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

viii

Contents

Abstract v

List of Publications vii

Contents viii

Abbreviations xi

1 Introduction 1

11 Palladium-catalyzed allylic CminusH acetoxylation 1

12 Synthesis of allylboronates 2

13 Application of allylboronates in synthesis 4

131 Stereoselective allylation of carbonyl compounds 4

132 Enantioselective allylation of carbonyl compounds 5

133 Stereoselective allylation of imines 9

2 Pd-catalyzed stereoselective allylic CminusH trifluoroacetoxylation (Paper I) 11

21 Development of selective intermolecular allylic CminusH

trifluoroacetoxylationhelliphelliphelliphellip 12

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation 15

23 Conclusions for the allylic CminusH trifluoroacetoxylation 17

3 Pd-catalyzed synthesis and isolation of allylboronic acids (Paper II) 18

31 Development of new synthetic methods for the synthesis and isolation of

allylboronic acids 18

311 Diboronic acid B2(OH)4 as boron source 19

312 Synthesis of allylboronic acids and their isolation 20

32 Characterization of allylboroxine 22

33 Proposed mechanism for the allylic CminusOH borylation 24

34 Conclusions for the allylic CminusOH borylation 25

4 Allylboration of carbonyl compounds using allylboronic acids (Paper II-III) 26

41 Allylation of ketones by allylboronic acids 26

42 Stereoselectivity of α-hydroxy acids 31

43 Conclusions for allylboration of carbonyl compounds 32

ix

5 Synthesis of adjacent quaternary stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV) 33

51 Method development for the asymmetric allylboration of ketones helliphellip33

52 Stereocontrol in the asymmetric allylboration of ketone 35

53 Catalytic enantioselective allylboration of ketones 36

54 Proposed mechanism for the enantioselectivity of the allylboration of

ketones with allylboronic acids 38

541 Proposed models for enantioselectivity 40

542 Proposed catalytic cycle 41

55 Conclusions for the catalytic asymmetric allylboration 42

6 Allylboration of imines indoles and hydrazones (Paper V-VI) 43

61 Allylation of imines with allylboronic acids 43

62 Allylation of indoles with allylboronic acids 46

63 Allylation of acyl hydrazones with allylboronic acids 48

64 Mechanistic study and proposal for the allylation of aldimines 50

65 Proposed mechanism for the allylboration of hydrazones 52

66 Proposed mechanism for the allylboration of indoles 54

67 Conclusions for the allylboration of imines indoles and hydrazones 55

7 Concluding remarks 56

8 Acknowledgements 57

9 Summary in Swedish 58

10 Appendix A 59

11 References 60

x

xi

Abbreviations

Abbreviations are used in agreement with standards of the subject1 Addi-

tional non-standard or unconventional abbreviations that appear in this thesis

are listed below

B2pin2 bis(pinacolato)diboron

BINOL 11-bi-2-naphthol

Bpin pinacolato boron

BQ 14-benzoquinone

dba dibenzylideneacetone

DFT density functional theory

DMC dimethyl carbonate

dr diastereomeric ratio

er enantiomeric ratio

LA Lewis acid

L ligand (neutral)

L chiral ligand

MS molecular sieves

NOE nuclear Overhauser effect

PIFA phenyliodine bis(trifluoroacetate)

PIDA phenyliodonium diacetate

TFA trifluoroacetate

TS transition state

rt room temperature

X ligand (charged)

1

1 Introduction

The development of highly selective transformations is of fundamental

importance in modern organic chemistry Transition metal-catalysis is one of

the useful synthetic approaches to achieve this goal2 The allylation reaction

using allylboron reagents and other allyl sources is also an important ap-

proach to develop selective syntheses3

11 Palladium-catalyzed allylic CminusH acetoxylation

Transition metal-catalyzed substitution of allylic acetates and their ana-

logs is one of the most utilized and studied reactions4 An important method

to synthesize allylic acetates is Pd-catalyzed allylic CminusH functionalization5

Pioneering works by McMurry and Kocovsky6 and Aringkermark

7 have shown

that Pd(II)-catalyzed allylic acetoxylation of cyclic and acyclic olefins can

be achieved in the presence of acetic acid and benzoquinone (BQ) as oxidant

(Scheme 1) Mechanistic investigations by Baumlckvall8 and co-workers

indicated that a (π-allyl)palladium(II) intermediates are involved in the

process and that BQ serves as both oxidant and activator ligand in the

CminusOAc bond formation process

Scheme 1 Pd-catalyzed allylic CminusH acetoxylation reaction

7a

Recently the White9 and the Stahl

10 group independently reported new

methods for CminusH acetoxylation reactions using palladium catalysis The

latter group used O2 as an oxidant instead of BQ According to the mechanis-

tic studies by these authors the CminusH acetoxylation process take place via

Pd0 and Pd

II catalytic intermediates

Hypervalent iodine reagents were also employed as the principal compo-

nent in the allylic CminusH oxidation reactions5 11

For example Szaboacute and

co-workers11b

have reported the allylic CminusH acyloxylation reaction with

PhI(OAc)2 (2a) as the oxidant and source of OAc (Scheme 2) The use of a

2

palladium catalysts and hypervalent iodine reagents allowed an easy access

to allylic acetoxy and benzoyloxy compounds Based on the mechanistic

studies a PdIIPd

IV catalytic cycle was proposed when PhI(OAc)2 was used

as the oxidant

Scheme 2 Pd-catalyzed CminusH acetoxylation reaction reported by Szaboacute and co-

workers11b

In spite of the wide application of allylic CminusH acyloxylation reactions in

organic synthesis the stereoselective transformations of substituted cyclic

alkenes are limited Particularly the intermolecular diastereoselective CminusH

acyloxylation is still a challenge A new synthetic process for such a reaction

is presented in Chapter 2

12 Synthesis of allylboronates

Allylboronates are efficient reagents for regio- and stereoselective allyla-

tion of carbonyl compounds and some related functionalities3 12

Due to the

importance of allylboronates in synthetic organic chemistry there has been a

large interest in the development of new methods for the synthesis of these

reagents The classical synthetic procedures involve application of allyl-

Grignard and allyl-Li reagents13

However these methods have a limited

synthetic scope because of problems with the regioselective formation of the

allylboronates Palladium-catalyzed methods based on the substitution of allylic alcohol

derivatives have proven to be a versatile and relatively simple method to

obtain allylboronates The first process was reported by Miyaura and

co-workers14

(Scheme 3) In this process B2pin2 was used as the boron

source Although the regioselectivity of the reaction is excellent a drawback

of this process is the formation of varying amounts of homocoupling prod-

ucts

Scheme 3 Pd-catalyzed borylation of allylacetates

14

The Szaboacute group15

has expanded the substrate scope to include allylic

alcohols instead of allylic acetates (Scheme 4) It was also shown that

3

certain Pd(II) pincer complexes are more efficient than Pd(dba)2 In depth

mechanistic studies revealed that catalytic amounts of Lewis or Broslashnsted

acids are required in the reaction to activate the allylic alcohols for Pd-

catalyzed substitution16

The reaction is substantially accelerated in the pres-

ence of MeOH or other protic co-solvents

Scheme 4 Pd-catalyzed borylation of allylic alcohols

15c 15d

The Szaboacute group also developed palladium-catalyzed allylic C-H boryla-

tion methods17

These processes allowed for the synthesis of allylboronates

from readily available alkenes under oxidative conditions using BQ (1) or

the hypervalent iodonium salt

Ito Sawamura and their co-workers reported the regio- and stereoselec-

tive synthesis of allylboronates by Cu-catalyzed substitution of allyl

carbonates18

This method can also be extended to asymmetric catalysis for

the synthesis of enantioenriched allylboronates (Scheme 5)19

Scheme 5 Cu-catalyzed asymmetric borylation of allylcarbonates

19

Enantioselective synthesis of α-substituted allylboronates has been

reported by Hall and co-workers (Scheme 6)20

This method is based on

copper-catalyzed substitution of allylhalide substrates The chiral

allylboronates generated in this reaction were used for further transformation

without isolation

Scheme 6 Cu-catalyzed borylation reported by Hall and co-workers

20

Related Cu-catalyzed asymmetric synthesis of allylboronates have also

been independently reported by the groups of Hoveyda21

and McQuade22

Nickel-catalyzed stereospecific borylation of allylic acetates was developed

by Morken and co-workers23

The reaction is highly selective for the termi-

4

nal allylboronates (Scheme 7) The Morken group also developed palladi-

um-catalyzed enantioselective borylation methods for the synthesis of al-

lylboronates24

Scheme 7 Ni-catalyzed selective borylation of allylic acetates

23

Very recently Aggarwal and co-workers have reported a new method for

the preparation of enantioenriched allylboronates25

This so called ldquolithia-

tion-borylation methodrdquo involves homologation of vinyl boronates using

alkyl carbamates and butyllithium (BuLi) in the presence of (+)-sparteine

(Scheme 8)

Scheme 8 Synthesis of allylboronates by lithiation-borylation method

25b

As shown above synthesis of allylboron reagents has attracted large in-

terest in modern organic chemistry As a contribution to this field we devel-

oped a new method for the synthesis and isolation of allylboronic acids

which is presented in Chapter 3

13 Application of allylboronates in synthesis

Allylboronate reagents have been extensively used to synthesize numerous precursors for natural products and bioactive molecules

26

Addition of allylboronates to carbonyl and imine electrophiles is a well studied and documented reactions in synthetic organic chemistry

131 Stereoselective allylation of carbonyl compounds

Allylboration reactions of aldehydes have been widely applied for the ste-

reoselective synthesis of homoallylic alcohols3 After the discovery by Bub-

nov27

the reaction was further developed by Hoffmann28

Brown29

Roush30

and others Hoffmann and Brown carried out in depth mechanistic studies

which also explained the stereochemistry of the reaction Hoffman postulat-

ed that the reaction between allylboronates and aldehydes proceeds via a six-

5

membered cyclic TS similar to the Zimmerman-Traxler31

model (Scheme

9)28a 32

The high diastereoselectivity of the allylboration reaction is attributed to

an internal Lewis acid activation of the carbonyl functionality by the empty

p-orbital of boron

Scheme 9 Zimmerman-Traxler model to describe stereochemistry of allylboration

reaction

The addition of Lewis or Broslashnsted acids may accelerate the allylboration

of carbonyl compounds33

Hall and co-workers proposed that Lewis acids

coordinate to the lone pair of the boronate oxygen which renders the boron

atom more electron deficient (Scheme 10)33b 34

This mechanism for LA

and Broslashnsted acid activation was also confirmed by the DFT studies of

Houk and co-workers35

Scheme 10 Possible modes of Lewis acid activation for the allylboration

Allylboronates can also react with ketones yielding tertiary homoallylic

alcohols However the addition of allylboronates to ketones is much slower

than similar reactions with aldehydes Thus the selective allylation of

ketones with allylboronates often requires the use of catalysts36

In addition

most of the present methods for allylboration of ketones are limited to the

use of unsubstituted (parent) allylboronates or crotylboronates

132 Enantioselective allylation of carbonyl compounds

There are basically two main approaches for the asymmetric allylboration

of carbonyl compounds The first approach is the application of enantioen-

riched allylboronates performing chirality transfer and the second one is

6

asymmetric induction by using chiral catalyst One of the first asymmetric

allylboration reactions was reported by Roush and co-workers 13b 37

These

authors employed chiral auxiliaries attached to the boron atom (Scheme 11)

Diisopropyl tartrate (DIPT) proved to be a very efficient chiral auxiliary to

induce enantioselectivity

Scheme 11 Asymmetric allylation of aldehydes using chiral allylboronate

13b

A similar approach was reported by Soderquist and co-workers38

for the

asymmetric allylboration of aldehyde and ketones A bicyclic chiral auxilia-

ry on the boron atom was employed for highly diastereo- and enantioselec-

tive allylboration (Scheme 12)

Scheme 12 Diastereo-and enantioselective allylboration by chiral allylborane

38a

Enantiomerically pure TADDOL based allylboronates were developed by

Pietruszka and co-workers39

These reagents were used for chirality transfer

in allylboration of aldehydes (Scheme 13) The chiral auxiliary can be

recovered after the allylation by reduction with LiAlH4

Scheme 13 Asymmetric allylation of aldehyde using enantiopure allylboronate

39

Metal-catalyzed asymmetric synthesis of heterocyclic allylboronates was

described by Hall and co-workers40

These allylboronates were used in situ

for allylboration of aldehydes The key-step in synthesis of mefloquine was

performed using this method (Scheme 14)

7

Scheme 14 Asymmetric allylboration by cyclic allylboronates

40

Very recently Aggarwal and co-workers25b 41

reported an efficient

allylboration method using α-substituted enantioenriched allylboronates (see

also Scheme 8) The method is highly diastereo- and enantioselective In

addition the procedure is suitable for the synthesis of homoallylic alcohols

with two adjacent quaternary stereocenters (Scheme 15)

Scheme 15 Asymmetric allylation of ketone by α-substituted chiral allylboronate

25b

An alternative approach for the asymmetric allylboration of carbonyl

compounds involves the application of chiral catalysts Both Lewis and

Broslashnsted acids have been used for the asymmetric allylboration reactions

The first catalytic enantioselective allylboration reaction was reported by

Miyaura and co-workers (Scheme 16)33c

This reaction proceeded with a

high regio- and diastereoselectivity but the enantioselectivity was relatively

low

Scheme 16 Catalytic asymmetric allylboration of aldehyde

33c

Hall and co-workers42

reported a Sn-catalyzed asymmetric allylboration

reaction using allyl-Bpin as the allyl source A chiral diol was used as a lig-

and in this process which was supposed to coordinate to SnCl4 (Scheme 17)

8

Scheme 17 Tin-catalyzed asymmetric allylboration of aldehyde

42a

Asymmetric allylation of ketones was reported using chiral allylboronate

derived from BINOL compounds Chong and co-workers described the al-

lylation of ketones using 33-(CF3)2-BINOL boronate 3a (Scheme 18)43

The

reaction gave homoallylic alcohol product with a high level of enantioselec-

tivity

Scheme 18 Asymmetric allylation of ketone using BINOL-boronate

43

Catalytic methods have also been described to control both diastereo- and

enantioselectivity in the allylboration of ketones44

The first catalytic

enantioselective allylboration of ketones was developed by Shibasaki and

co-workers45

Broslashnsted acid such as BINOL derivatives44 46

was found to be

very efficient in the asymmetric allylboration reactions Schaus and

co-workers44

reported a method for asymmetric allylation of ketones using

isopropoxyboronate and catalytic amounts of Br2-BINOL 4a (Scheme 19)

Scheme 19 Catalytic asymmetric allylboration of ketone using Br2-BINOL

44a

These authors proposed a Zimmerman-Traxler type transition state to

rationalize the enantioselectivity in this reaction It has been also pointed out

that the substituent in BINOL (eg Br or CF3) has an important role for the

enantioselectivity of these reactions

Catalytic synthesis of homoallylic alcohols containing adjacent quater-

nary stereocenters has been a great challenge in synthetic organic chemistry

A new synthetic method for such reaction is presented in Section 52

9

133 Stereoselective allylation of imines

Homoallylic amine motifs occur in many natural products and biological-

ly relevant compounds47

One of the most common strategies for homoallylic

amine synthesis is the addition of allyl-metal reagents to imines48

The use of

allylboronate compounds for these reactions has emerged as an important

synthetic approach47

Allylboronates have a low toxicity high functional

group tolerance and the allylation of imines occurs with a high level of

selectivity

Stereoselective allylation of aldimines can be performed by

allylboronates in the presence of Lewis acid catalysts Batey and

co-workers49

reported the allylboration of N-toluenesulfonylimines using

crotyltrifluroboronate and BF3OEt2 (Scheme 20) The allylation was

proposed to proceed via the allyl-BF2 species which is generated from

allyl-BF3K

Scheme 20 Stereoselective allylation of imine by allyltrifluoroborate

49

Kobayashi and co-workers50

reported a three-component diastereoselec-

tive allylation reaction to synthesize homoallylic primary amines (Scheme

21) In addition several useful methods for asymmetric allylboration of

imines25b 51

using allylboronates can also be found in literature

Scheme 21 Synthesis of homoallylic amine using multicomponent method

50

Allylboration of acylhydrazones have also proven to be a very useful

reaction for the synthesis of homoallylic amine derivatives However the

allylation of acylhydrazones by allylboronates requires the application of

metal catalysts52

An indium-catalyzed reaction for the allylation of N-

acylhydrazone was reported by Kobayashi and co-workers (Scheme 22)52a

It

has been proposed that indium undergoes a transmetallation with allyl-Bpin

to form an active allyl-indium species which then added to the hydrazone

10

Scheme 22 Indium-catalyzed allylation of acylhydrazone

52a

We have developed a stereoselective method for allylation of imines and

acylhydrazones using allylboronic acids These results are summarized in

Chapter 6

11

2 Pd-catalyzed stereoselective allylic CminusH

trifluoroacetoxylation (Paper I)

As mentioned in the introduction transition metal-catalyzed CminusH bond activation methods have attracted increasing interest in organic synthesis

53

Using these methods multistep synthesis for prefunctionalization of the or-ganic substrates is not necessary In addition the waste production of the reaction can be reduced as the new functional group can be installed by re-placement of hydrogen

54 Palladium-catalyzed allylic CminusH bond activation is

one of the oldest and most versatile CminusH functionalization method (Section 11)

55 In this reaction (as in CminusH activation based processes in general) the

greatest challenge is the control of the regio- and stereoselectivity of the process

Stereodefined allylic acetates are very important precursors for regio- and stereoselective palladium-catalyzed allylic substitution reactions

56 Although

many regioselective allylic CminusH functionalization methods have been re-ported there are few reports on stereoselective allylic CminusH acetoxylation

7a

Most of these studies are intramolecular CminusH acyloxylation reactions For example a stereoselective allylic CminusH acetoxylation method has been re-ported by White and co-workers (Scheme 23) Intramolecular selectivity control allowed macrocyclization

57 and straightforward synthesis of anti-14-

dioxan-2-ones58

from simple olefins using Pd(II)sulfoxide catalysis Baumlck-vall and co-workers

59 have also developed several methods for the synthesis

of allylacetoxy compounds based on palladium-catalyzed intramolecular oxidative carbocyclization

Scheme 23 Stereoselective intramolecular CminusH oxidation reported by White and

co-workers58

12

21 Development of selective intermolecular allylic CminusH trifluoroacetoxylation

As our group previously developed a useful allylic CminusH acetoxylation

method based on using PhI(OAc)2 (2a) (see Section 11) as oxidant and ace-

tate source we envisioned that PhI(OCOCF3)2 (2b) can also be used in this

type of reaction to introduce a trifluoroacetate group at the allylic position of

alkenes Allylic trifluoroacetates are more reactive than allylic acetates in

transition metal-catalyzed substitutions60

and therefore an easy access to

these compounds is desirable As far as we know selective allylic CminusH tri-

fluoroacetoxylation has not been reported in the literature

In the early stage of development and optimization we employed car-

boxylated alkene 6a as our model substrate as it gave a high yield and ex-

hibited high selectivity in the Pd-catalyzed CminusH acetoxylation with 2a11b

However PhI(OCOCF3)2 (2b) is most likely a stronger oxidant than

PhI(OAc)2 (2a) and therefore we could not use oxidation sensitive solvents

such as THF or DMSO In addition the conjugated acid of the trifluoroace-

tate ion (the nucleophile) is a strong acid and therefore trifluoroacetic acid

could not be used as the solvent either After short optimization we have

found that dimethyl carbonate (DMC) is an excellent solvent for all reaction

components and it is not oxidized by PIFA We have found that the isolated

yields are higher when LiOCOCF3 is used as additive Under these condi-

tions the reaction could be performed with various functionalized alkenes

(Table 1)

13

Table 1 Pd-catalyzed allylic CminusH trifluoroacetoxylation of acyclic olefinsa

Both Pd(OAc)2 (5b) and Pd(OCOCF3)2 (5c) were equally efficient as cat-

alyst in the reaction So we decided to use 5b in the present synthetic method

as it is less expensive than 5c Not only terminal (6a) but internal alkenes

6b-c could also be used for trifluoroacetoxylation with high selectivity Oth-

er alkenes with electron withdrawing substituents such as 6d-e could also be

smoothly trifluoroacetoxylated Substrates without electron-withdrawing

groups gave intractable mixtures of trifluoroacetoxylated products For com-

pounds with long alkyl chain oxidation of the double bond occurred while in

the case of electron donating substituents mainly oxidation of the double

bond occurred together with other processes

14

Table 2 Stereoselective allylic CminusH trifluoroacetoxylation of cyclic alkenesa

Not only acyclic alkenes but cyclic alkenes could also be employed for

the trifluoroacetoxylation reaction Monosubstituted cyclic alkenes reacted

with a remarkably high selectivity (Table 2) The reaction conditions were

very similar to the trifluoroacetoxylation of acyclic substrates (Table 1) but

in order to get this high stereoselectivity the reactions had to be conducted

at 0 degC This is below the freezing point of DMC therefore the reaction me-

dium was diluted with DCM to avoid freezing of the reaction mixture The

yields with LiOCOCF3 were as high as in its absence therefore we did not

use this additive in the trifluoroacetoxylation of cyclic substrates

Considering the number of possible regio- and stereoisomers a mixture

of six allylic trifluoroacetate products could be expected Yet in most cases

we obtained a single diastereomer with very high regioselectivity (Table 2

entries 1-2 and 4-5) The major regioisomer in all cases was the 14-

substituted product (7f-j) with anti diastereoselectivity and the minor prod-

uct is the regioisomer of the same diastereomer The stereochemistry of the

major isomers was assigned based on NOE experiments

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

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83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

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iii

আমমাrsquoকেmdashকে আমাকে দrsquoটি টিনন অনধোর কেকে আক া কদটিকেকে

এবং আববাrsquoকেmdashধরব োো হকে আকেন টেটন

To my parents

iv

v

Abstract

This thesis is focused on two main areas of organic synthesis palladium-

catalyzed functionalization of alkenes and allylic alcohols as well as devel-

opment of new allylboration reactions

We have developed a palladium-catalyzed selective allylic trifluoroace-

toxylation reaction based on CminusH functionalization Allylic trifluoroacetates

were synthesized from functionalized olefins under oxidative conditions

The reactions proceed under mild conditions with a high level of diastereose-

lectivity Mechanistic studies of the allylic CminusH trifluoroacetoxylation

indicate that the reaction proceeds via (η3-allyl)palladium(IV) intermediate

Palladium-catalyzed regio- and stereoselective synthesis of allylboronic

acids from allylic alcohols has been demonstrated Diboronic acid B2(OH)4

was used as the boron source in this process

The reactivity of the allylboronic acids were studied in three types of

allylboration reactions allylboration of ketones imines and acyl hydrazones

All three processes are conducted under mild conditions without any

additives The reactions proceeded with remarkably high regio- and stereose-

lectivity

An asymmetric version of the allylboration of ketones was also devel-

oped In this process chiral BINOL derivatives were used as catalysts The

reaction using γ-disubstituted allylboronic acids and various aromatic and

aliphatic ketones afforded homoallylic alcohols bearing two adjacent quater-

nary stereocenters with excellent regio- diastereo- and enantioselectivity (up

to 973 er) in high yield The stereoselectivity in the allylboration reactions

could be rationalized on the basis of the Zimmerman-Traxler TS model

vi

vii

List of Publications

This thesis is based on a licentiate thesis by Rauful Alam entitled ldquoPalladi-

um-catalyzed Allylic CminusH and CminusOH Functionalization Reactions of the

Obtained Allylboronic Acidsrdquo and the following papers referred to in text

by their Roman numerals I-VI Reprints were made with the kind permission

from the publishers (Appendix A)

I Stereoselective Intermolecular Allylic C-H Trifluoroacetoxylation

of Functionalized Alkenes

Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

II Palladium-Catalyzed Synthesis and Isolation of Functionalized

Allylboronic Acids Facile Direct Allylboration of Ketones Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

III Selective Formation of Adjacent Stereocenters by Allylboration of

Ketones under Mild Neutral Conditions Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

IV Synthesis of Adjacent Quaternary Stereocenters by Catalytic

Asymmetric Allylboration

Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

V Stereoselective Allylboration of Imines and Indoles under Mild

Conditions An in situ EZ Isomerization of Imines by Allylborox-

ines Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

VI Stereocontrol in Synthesis of Homoallylic Amines Syn Selective

Direct Allylation of Hydrazones with Allylboronic Acids Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

viii

Contents

Abstract v

List of Publications vii

Contents viii

Abbreviations xi

1 Introduction 1

11 Palladium-catalyzed allylic CminusH acetoxylation 1

12 Synthesis of allylboronates 2

13 Application of allylboronates in synthesis 4

131 Stereoselective allylation of carbonyl compounds 4

132 Enantioselective allylation of carbonyl compounds 5

133 Stereoselective allylation of imines 9

2 Pd-catalyzed stereoselective allylic CminusH trifluoroacetoxylation (Paper I) 11

21 Development of selective intermolecular allylic CminusH

trifluoroacetoxylationhelliphelliphelliphellip 12

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation 15

23 Conclusions for the allylic CminusH trifluoroacetoxylation 17

3 Pd-catalyzed synthesis and isolation of allylboronic acids (Paper II) 18

31 Development of new synthetic methods for the synthesis and isolation of

allylboronic acids 18

311 Diboronic acid B2(OH)4 as boron source 19

312 Synthesis of allylboronic acids and their isolation 20

32 Characterization of allylboroxine 22

33 Proposed mechanism for the allylic CminusOH borylation 24

34 Conclusions for the allylic CminusOH borylation 25

4 Allylboration of carbonyl compounds using allylboronic acids (Paper II-III) 26

41 Allylation of ketones by allylboronic acids 26

42 Stereoselectivity of α-hydroxy acids 31

43 Conclusions for allylboration of carbonyl compounds 32

ix

5 Synthesis of adjacent quaternary stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV) 33

51 Method development for the asymmetric allylboration of ketones helliphellip33

52 Stereocontrol in the asymmetric allylboration of ketone 35

53 Catalytic enantioselective allylboration of ketones 36

54 Proposed mechanism for the enantioselectivity of the allylboration of

ketones with allylboronic acids 38

541 Proposed models for enantioselectivity 40

542 Proposed catalytic cycle 41

55 Conclusions for the catalytic asymmetric allylboration 42

6 Allylboration of imines indoles and hydrazones (Paper V-VI) 43

61 Allylation of imines with allylboronic acids 43

62 Allylation of indoles with allylboronic acids 46

63 Allylation of acyl hydrazones with allylboronic acids 48

64 Mechanistic study and proposal for the allylation of aldimines 50

65 Proposed mechanism for the allylboration of hydrazones 52

66 Proposed mechanism for the allylboration of indoles 54

67 Conclusions for the allylboration of imines indoles and hydrazones 55

7 Concluding remarks 56

8 Acknowledgements 57

9 Summary in Swedish 58

10 Appendix A 59

11 References 60

x

xi

Abbreviations

Abbreviations are used in agreement with standards of the subject1 Addi-

tional non-standard or unconventional abbreviations that appear in this thesis

are listed below

B2pin2 bis(pinacolato)diboron

BINOL 11-bi-2-naphthol

Bpin pinacolato boron

BQ 14-benzoquinone

dba dibenzylideneacetone

DFT density functional theory

DMC dimethyl carbonate

dr diastereomeric ratio

er enantiomeric ratio

LA Lewis acid

L ligand (neutral)

L chiral ligand

MS molecular sieves

NOE nuclear Overhauser effect

PIFA phenyliodine bis(trifluoroacetate)

PIDA phenyliodonium diacetate

TFA trifluoroacetate

TS transition state

rt room temperature

X ligand (charged)

1

1 Introduction

The development of highly selective transformations is of fundamental

importance in modern organic chemistry Transition metal-catalysis is one of

the useful synthetic approaches to achieve this goal2 The allylation reaction

using allylboron reagents and other allyl sources is also an important ap-

proach to develop selective syntheses3

11 Palladium-catalyzed allylic CminusH acetoxylation

Transition metal-catalyzed substitution of allylic acetates and their ana-

logs is one of the most utilized and studied reactions4 An important method

to synthesize allylic acetates is Pd-catalyzed allylic CminusH functionalization5

Pioneering works by McMurry and Kocovsky6 and Aringkermark

7 have shown

that Pd(II)-catalyzed allylic acetoxylation of cyclic and acyclic olefins can

be achieved in the presence of acetic acid and benzoquinone (BQ) as oxidant

(Scheme 1) Mechanistic investigations by Baumlckvall8 and co-workers

indicated that a (π-allyl)palladium(II) intermediates are involved in the

process and that BQ serves as both oxidant and activator ligand in the

CminusOAc bond formation process

Scheme 1 Pd-catalyzed allylic CminusH acetoxylation reaction

7a

Recently the White9 and the Stahl

10 group independently reported new

methods for CminusH acetoxylation reactions using palladium catalysis The

latter group used O2 as an oxidant instead of BQ According to the mechanis-

tic studies by these authors the CminusH acetoxylation process take place via

Pd0 and Pd

II catalytic intermediates

Hypervalent iodine reagents were also employed as the principal compo-

nent in the allylic CminusH oxidation reactions5 11

For example Szaboacute and

co-workers11b

have reported the allylic CminusH acyloxylation reaction with

PhI(OAc)2 (2a) as the oxidant and source of OAc (Scheme 2) The use of a

2

palladium catalysts and hypervalent iodine reagents allowed an easy access

to allylic acetoxy and benzoyloxy compounds Based on the mechanistic

studies a PdIIPd

IV catalytic cycle was proposed when PhI(OAc)2 was used

as the oxidant

Scheme 2 Pd-catalyzed CminusH acetoxylation reaction reported by Szaboacute and co-

workers11b

In spite of the wide application of allylic CminusH acyloxylation reactions in

organic synthesis the stereoselective transformations of substituted cyclic

alkenes are limited Particularly the intermolecular diastereoselective CminusH

acyloxylation is still a challenge A new synthetic process for such a reaction

is presented in Chapter 2

12 Synthesis of allylboronates

Allylboronates are efficient reagents for regio- and stereoselective allyla-

tion of carbonyl compounds and some related functionalities3 12

Due to the

importance of allylboronates in synthetic organic chemistry there has been a

large interest in the development of new methods for the synthesis of these

reagents The classical synthetic procedures involve application of allyl-

Grignard and allyl-Li reagents13

However these methods have a limited

synthetic scope because of problems with the regioselective formation of the

allylboronates Palladium-catalyzed methods based on the substitution of allylic alcohol

derivatives have proven to be a versatile and relatively simple method to

obtain allylboronates The first process was reported by Miyaura and

co-workers14

(Scheme 3) In this process B2pin2 was used as the boron

source Although the regioselectivity of the reaction is excellent a drawback

of this process is the formation of varying amounts of homocoupling prod-

ucts

Scheme 3 Pd-catalyzed borylation of allylacetates

14

The Szaboacute group15

has expanded the substrate scope to include allylic

alcohols instead of allylic acetates (Scheme 4) It was also shown that

3

certain Pd(II) pincer complexes are more efficient than Pd(dba)2 In depth

mechanistic studies revealed that catalytic amounts of Lewis or Broslashnsted

acids are required in the reaction to activate the allylic alcohols for Pd-

catalyzed substitution16

The reaction is substantially accelerated in the pres-

ence of MeOH or other protic co-solvents

Scheme 4 Pd-catalyzed borylation of allylic alcohols

15c 15d

The Szaboacute group also developed palladium-catalyzed allylic C-H boryla-

tion methods17

These processes allowed for the synthesis of allylboronates

from readily available alkenes under oxidative conditions using BQ (1) or

the hypervalent iodonium salt

Ito Sawamura and their co-workers reported the regio- and stereoselec-

tive synthesis of allylboronates by Cu-catalyzed substitution of allyl

carbonates18

This method can also be extended to asymmetric catalysis for

the synthesis of enantioenriched allylboronates (Scheme 5)19

Scheme 5 Cu-catalyzed asymmetric borylation of allylcarbonates

19

Enantioselective synthesis of α-substituted allylboronates has been

reported by Hall and co-workers (Scheme 6)20

This method is based on

copper-catalyzed substitution of allylhalide substrates The chiral

allylboronates generated in this reaction were used for further transformation

without isolation

Scheme 6 Cu-catalyzed borylation reported by Hall and co-workers

20

Related Cu-catalyzed asymmetric synthesis of allylboronates have also

been independently reported by the groups of Hoveyda21

and McQuade22

Nickel-catalyzed stereospecific borylation of allylic acetates was developed

by Morken and co-workers23

The reaction is highly selective for the termi-

4

nal allylboronates (Scheme 7) The Morken group also developed palladi-

um-catalyzed enantioselective borylation methods for the synthesis of al-

lylboronates24

Scheme 7 Ni-catalyzed selective borylation of allylic acetates

23

Very recently Aggarwal and co-workers have reported a new method for

the preparation of enantioenriched allylboronates25

This so called ldquolithia-

tion-borylation methodrdquo involves homologation of vinyl boronates using

alkyl carbamates and butyllithium (BuLi) in the presence of (+)-sparteine

(Scheme 8)

Scheme 8 Synthesis of allylboronates by lithiation-borylation method

25b

As shown above synthesis of allylboron reagents has attracted large in-

terest in modern organic chemistry As a contribution to this field we devel-

oped a new method for the synthesis and isolation of allylboronic acids

which is presented in Chapter 3

13 Application of allylboronates in synthesis

Allylboronate reagents have been extensively used to synthesize numerous precursors for natural products and bioactive molecules

26

Addition of allylboronates to carbonyl and imine electrophiles is a well studied and documented reactions in synthetic organic chemistry

131 Stereoselective allylation of carbonyl compounds

Allylboration reactions of aldehydes have been widely applied for the ste-

reoselective synthesis of homoallylic alcohols3 After the discovery by Bub-

nov27

the reaction was further developed by Hoffmann28

Brown29

Roush30

and others Hoffmann and Brown carried out in depth mechanistic studies

which also explained the stereochemistry of the reaction Hoffman postulat-

ed that the reaction between allylboronates and aldehydes proceeds via a six-

5

membered cyclic TS similar to the Zimmerman-Traxler31

model (Scheme

9)28a 32

The high diastereoselectivity of the allylboration reaction is attributed to

an internal Lewis acid activation of the carbonyl functionality by the empty

p-orbital of boron

Scheme 9 Zimmerman-Traxler model to describe stereochemistry of allylboration

reaction

The addition of Lewis or Broslashnsted acids may accelerate the allylboration

of carbonyl compounds33

Hall and co-workers proposed that Lewis acids

coordinate to the lone pair of the boronate oxygen which renders the boron

atom more electron deficient (Scheme 10)33b 34

This mechanism for LA

and Broslashnsted acid activation was also confirmed by the DFT studies of

Houk and co-workers35

Scheme 10 Possible modes of Lewis acid activation for the allylboration

Allylboronates can also react with ketones yielding tertiary homoallylic

alcohols However the addition of allylboronates to ketones is much slower

than similar reactions with aldehydes Thus the selective allylation of

ketones with allylboronates often requires the use of catalysts36

In addition

most of the present methods for allylboration of ketones are limited to the

use of unsubstituted (parent) allylboronates or crotylboronates

132 Enantioselective allylation of carbonyl compounds

There are basically two main approaches for the asymmetric allylboration

of carbonyl compounds The first approach is the application of enantioen-

riched allylboronates performing chirality transfer and the second one is

6

asymmetric induction by using chiral catalyst One of the first asymmetric

allylboration reactions was reported by Roush and co-workers 13b 37

These

authors employed chiral auxiliaries attached to the boron atom (Scheme 11)

Diisopropyl tartrate (DIPT) proved to be a very efficient chiral auxiliary to

induce enantioselectivity

Scheme 11 Asymmetric allylation of aldehydes using chiral allylboronate

13b

A similar approach was reported by Soderquist and co-workers38

for the

asymmetric allylboration of aldehyde and ketones A bicyclic chiral auxilia-

ry on the boron atom was employed for highly diastereo- and enantioselec-

tive allylboration (Scheme 12)

Scheme 12 Diastereo-and enantioselective allylboration by chiral allylborane

38a

Enantiomerically pure TADDOL based allylboronates were developed by

Pietruszka and co-workers39

These reagents were used for chirality transfer

in allylboration of aldehydes (Scheme 13) The chiral auxiliary can be

recovered after the allylation by reduction with LiAlH4

Scheme 13 Asymmetric allylation of aldehyde using enantiopure allylboronate

39

Metal-catalyzed asymmetric synthesis of heterocyclic allylboronates was

described by Hall and co-workers40

These allylboronates were used in situ

for allylboration of aldehydes The key-step in synthesis of mefloquine was

performed using this method (Scheme 14)

7

Scheme 14 Asymmetric allylboration by cyclic allylboronates

40

Very recently Aggarwal and co-workers25b 41

reported an efficient

allylboration method using α-substituted enantioenriched allylboronates (see

also Scheme 8) The method is highly diastereo- and enantioselective In

addition the procedure is suitable for the synthesis of homoallylic alcohols

with two adjacent quaternary stereocenters (Scheme 15)

Scheme 15 Asymmetric allylation of ketone by α-substituted chiral allylboronate

25b

An alternative approach for the asymmetric allylboration of carbonyl

compounds involves the application of chiral catalysts Both Lewis and

Broslashnsted acids have been used for the asymmetric allylboration reactions

The first catalytic enantioselective allylboration reaction was reported by

Miyaura and co-workers (Scheme 16)33c

This reaction proceeded with a

high regio- and diastereoselectivity but the enantioselectivity was relatively

low

Scheme 16 Catalytic asymmetric allylboration of aldehyde

33c

Hall and co-workers42

reported a Sn-catalyzed asymmetric allylboration

reaction using allyl-Bpin as the allyl source A chiral diol was used as a lig-

and in this process which was supposed to coordinate to SnCl4 (Scheme 17)

8

Scheme 17 Tin-catalyzed asymmetric allylboration of aldehyde

42a

Asymmetric allylation of ketones was reported using chiral allylboronate

derived from BINOL compounds Chong and co-workers described the al-

lylation of ketones using 33-(CF3)2-BINOL boronate 3a (Scheme 18)43

The

reaction gave homoallylic alcohol product with a high level of enantioselec-

tivity

Scheme 18 Asymmetric allylation of ketone using BINOL-boronate

43

Catalytic methods have also been described to control both diastereo- and

enantioselectivity in the allylboration of ketones44

The first catalytic

enantioselective allylboration of ketones was developed by Shibasaki and

co-workers45

Broslashnsted acid such as BINOL derivatives44 46

was found to be

very efficient in the asymmetric allylboration reactions Schaus and

co-workers44

reported a method for asymmetric allylation of ketones using

isopropoxyboronate and catalytic amounts of Br2-BINOL 4a (Scheme 19)

Scheme 19 Catalytic asymmetric allylboration of ketone using Br2-BINOL

44a

These authors proposed a Zimmerman-Traxler type transition state to

rationalize the enantioselectivity in this reaction It has been also pointed out

that the substituent in BINOL (eg Br or CF3) has an important role for the

enantioselectivity of these reactions

Catalytic synthesis of homoallylic alcohols containing adjacent quater-

nary stereocenters has been a great challenge in synthetic organic chemistry

A new synthetic method for such reaction is presented in Section 52

9

133 Stereoselective allylation of imines

Homoallylic amine motifs occur in many natural products and biological-

ly relevant compounds47

One of the most common strategies for homoallylic

amine synthesis is the addition of allyl-metal reagents to imines48

The use of

allylboronate compounds for these reactions has emerged as an important

synthetic approach47

Allylboronates have a low toxicity high functional

group tolerance and the allylation of imines occurs with a high level of

selectivity

Stereoselective allylation of aldimines can be performed by

allylboronates in the presence of Lewis acid catalysts Batey and

co-workers49

reported the allylboration of N-toluenesulfonylimines using

crotyltrifluroboronate and BF3OEt2 (Scheme 20) The allylation was

proposed to proceed via the allyl-BF2 species which is generated from

allyl-BF3K

Scheme 20 Stereoselective allylation of imine by allyltrifluoroborate

49

Kobayashi and co-workers50

reported a three-component diastereoselec-

tive allylation reaction to synthesize homoallylic primary amines (Scheme

21) In addition several useful methods for asymmetric allylboration of

imines25b 51

using allylboronates can also be found in literature

Scheme 21 Synthesis of homoallylic amine using multicomponent method

50

Allylboration of acylhydrazones have also proven to be a very useful

reaction for the synthesis of homoallylic amine derivatives However the

allylation of acylhydrazones by allylboronates requires the application of

metal catalysts52

An indium-catalyzed reaction for the allylation of N-

acylhydrazone was reported by Kobayashi and co-workers (Scheme 22)52a

It

has been proposed that indium undergoes a transmetallation with allyl-Bpin

to form an active allyl-indium species which then added to the hydrazone

10

Scheme 22 Indium-catalyzed allylation of acylhydrazone

52a

We have developed a stereoselective method for allylation of imines and

acylhydrazones using allylboronic acids These results are summarized in

Chapter 6

11

2 Pd-catalyzed stereoselective allylic CminusH

trifluoroacetoxylation (Paper I)

As mentioned in the introduction transition metal-catalyzed CminusH bond activation methods have attracted increasing interest in organic synthesis

53

Using these methods multistep synthesis for prefunctionalization of the or-ganic substrates is not necessary In addition the waste production of the reaction can be reduced as the new functional group can be installed by re-placement of hydrogen

54 Palladium-catalyzed allylic CminusH bond activation is

one of the oldest and most versatile CminusH functionalization method (Section 11)

55 In this reaction (as in CminusH activation based processes in general) the

greatest challenge is the control of the regio- and stereoselectivity of the process

Stereodefined allylic acetates are very important precursors for regio- and stereoselective palladium-catalyzed allylic substitution reactions

56 Although

many regioselective allylic CminusH functionalization methods have been re-ported there are few reports on stereoselective allylic CminusH acetoxylation

7a

Most of these studies are intramolecular CminusH acyloxylation reactions For example a stereoselective allylic CminusH acetoxylation method has been re-ported by White and co-workers (Scheme 23) Intramolecular selectivity control allowed macrocyclization

57 and straightforward synthesis of anti-14-

dioxan-2-ones58

from simple olefins using Pd(II)sulfoxide catalysis Baumlck-vall and co-workers

59 have also developed several methods for the synthesis

of allylacetoxy compounds based on palladium-catalyzed intramolecular oxidative carbocyclization

Scheme 23 Stereoselective intramolecular CminusH oxidation reported by White and

co-workers58

12

21 Development of selective intermolecular allylic CminusH trifluoroacetoxylation

As our group previously developed a useful allylic CminusH acetoxylation

method based on using PhI(OAc)2 (2a) (see Section 11) as oxidant and ace-

tate source we envisioned that PhI(OCOCF3)2 (2b) can also be used in this

type of reaction to introduce a trifluoroacetate group at the allylic position of

alkenes Allylic trifluoroacetates are more reactive than allylic acetates in

transition metal-catalyzed substitutions60

and therefore an easy access to

these compounds is desirable As far as we know selective allylic CminusH tri-

fluoroacetoxylation has not been reported in the literature

In the early stage of development and optimization we employed car-

boxylated alkene 6a as our model substrate as it gave a high yield and ex-

hibited high selectivity in the Pd-catalyzed CminusH acetoxylation with 2a11b

However PhI(OCOCF3)2 (2b) is most likely a stronger oxidant than

PhI(OAc)2 (2a) and therefore we could not use oxidation sensitive solvents

such as THF or DMSO In addition the conjugated acid of the trifluoroace-

tate ion (the nucleophile) is a strong acid and therefore trifluoroacetic acid

could not be used as the solvent either After short optimization we have

found that dimethyl carbonate (DMC) is an excellent solvent for all reaction

components and it is not oxidized by PIFA We have found that the isolated

yields are higher when LiOCOCF3 is used as additive Under these condi-

tions the reaction could be performed with various functionalized alkenes

(Table 1)

13

Table 1 Pd-catalyzed allylic CminusH trifluoroacetoxylation of acyclic olefinsa

Both Pd(OAc)2 (5b) and Pd(OCOCF3)2 (5c) were equally efficient as cat-

alyst in the reaction So we decided to use 5b in the present synthetic method

as it is less expensive than 5c Not only terminal (6a) but internal alkenes

6b-c could also be used for trifluoroacetoxylation with high selectivity Oth-

er alkenes with electron withdrawing substituents such as 6d-e could also be

smoothly trifluoroacetoxylated Substrates without electron-withdrawing

groups gave intractable mixtures of trifluoroacetoxylated products For com-

pounds with long alkyl chain oxidation of the double bond occurred while in

the case of electron donating substituents mainly oxidation of the double

bond occurred together with other processes

14

Table 2 Stereoselective allylic CminusH trifluoroacetoxylation of cyclic alkenesa

Not only acyclic alkenes but cyclic alkenes could also be employed for

the trifluoroacetoxylation reaction Monosubstituted cyclic alkenes reacted

with a remarkably high selectivity (Table 2) The reaction conditions were

very similar to the trifluoroacetoxylation of acyclic substrates (Table 1) but

in order to get this high stereoselectivity the reactions had to be conducted

at 0 degC This is below the freezing point of DMC therefore the reaction me-

dium was diluted with DCM to avoid freezing of the reaction mixture The

yields with LiOCOCF3 were as high as in its absence therefore we did not

use this additive in the trifluoroacetoxylation of cyclic substrates

Considering the number of possible regio- and stereoisomers a mixture

of six allylic trifluoroacetate products could be expected Yet in most cases

we obtained a single diastereomer with very high regioselectivity (Table 2

entries 1-2 and 4-5) The major regioisomer in all cases was the 14-

substituted product (7f-j) with anti diastereoselectivity and the minor prod-

uct is the regioisomer of the same diastereomer The stereochemistry of the

major isomers was assigned based on NOE experiments

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

1 The ACS Style Guide 3rd ed Oxford University Press New York 2006

2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

iv

v

Abstract

This thesis is focused on two main areas of organic synthesis palladium-

catalyzed functionalization of alkenes and allylic alcohols as well as devel-

opment of new allylboration reactions

We have developed a palladium-catalyzed selective allylic trifluoroace-

toxylation reaction based on CminusH functionalization Allylic trifluoroacetates

were synthesized from functionalized olefins under oxidative conditions

The reactions proceed under mild conditions with a high level of diastereose-

lectivity Mechanistic studies of the allylic CminusH trifluoroacetoxylation

indicate that the reaction proceeds via (η3-allyl)palladium(IV) intermediate

Palladium-catalyzed regio- and stereoselective synthesis of allylboronic

acids from allylic alcohols has been demonstrated Diboronic acid B2(OH)4

was used as the boron source in this process

The reactivity of the allylboronic acids were studied in three types of

allylboration reactions allylboration of ketones imines and acyl hydrazones

All three processes are conducted under mild conditions without any

additives The reactions proceeded with remarkably high regio- and stereose-

lectivity

An asymmetric version of the allylboration of ketones was also devel-

oped In this process chiral BINOL derivatives were used as catalysts The

reaction using γ-disubstituted allylboronic acids and various aromatic and

aliphatic ketones afforded homoallylic alcohols bearing two adjacent quater-

nary stereocenters with excellent regio- diastereo- and enantioselectivity (up

to 973 er) in high yield The stereoselectivity in the allylboration reactions

could be rationalized on the basis of the Zimmerman-Traxler TS model

vi

vii

List of Publications

This thesis is based on a licentiate thesis by Rauful Alam entitled ldquoPalladi-

um-catalyzed Allylic CminusH and CminusOH Functionalization Reactions of the

Obtained Allylboronic Acidsrdquo and the following papers referred to in text

by their Roman numerals I-VI Reprints were made with the kind permission

from the publishers (Appendix A)

I Stereoselective Intermolecular Allylic C-H Trifluoroacetoxylation

of Functionalized Alkenes

Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

II Palladium-Catalyzed Synthesis and Isolation of Functionalized

Allylboronic Acids Facile Direct Allylboration of Ketones Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

III Selective Formation of Adjacent Stereocenters by Allylboration of

Ketones under Mild Neutral Conditions Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

IV Synthesis of Adjacent Quaternary Stereocenters by Catalytic

Asymmetric Allylboration

Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

V Stereoselective Allylboration of Imines and Indoles under Mild

Conditions An in situ EZ Isomerization of Imines by Allylborox-

ines Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

VI Stereocontrol in Synthesis of Homoallylic Amines Syn Selective

Direct Allylation of Hydrazones with Allylboronic Acids Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

viii

Contents

Abstract v

List of Publications vii

Contents viii

Abbreviations xi

1 Introduction 1

11 Palladium-catalyzed allylic CminusH acetoxylation 1

12 Synthesis of allylboronates 2

13 Application of allylboronates in synthesis 4

131 Stereoselective allylation of carbonyl compounds 4

132 Enantioselective allylation of carbonyl compounds 5

133 Stereoselective allylation of imines 9

2 Pd-catalyzed stereoselective allylic CminusH trifluoroacetoxylation (Paper I) 11

21 Development of selective intermolecular allylic CminusH

trifluoroacetoxylationhelliphelliphelliphellip 12

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation 15

23 Conclusions for the allylic CminusH trifluoroacetoxylation 17

3 Pd-catalyzed synthesis and isolation of allylboronic acids (Paper II) 18

31 Development of new synthetic methods for the synthesis and isolation of

allylboronic acids 18

311 Diboronic acid B2(OH)4 as boron source 19

312 Synthesis of allylboronic acids and their isolation 20

32 Characterization of allylboroxine 22

33 Proposed mechanism for the allylic CminusOH borylation 24

34 Conclusions for the allylic CminusOH borylation 25

4 Allylboration of carbonyl compounds using allylboronic acids (Paper II-III) 26

41 Allylation of ketones by allylboronic acids 26

42 Stereoselectivity of α-hydroxy acids 31

43 Conclusions for allylboration of carbonyl compounds 32

ix

5 Synthesis of adjacent quaternary stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV) 33

51 Method development for the asymmetric allylboration of ketones helliphellip33

52 Stereocontrol in the asymmetric allylboration of ketone 35

53 Catalytic enantioselective allylboration of ketones 36

54 Proposed mechanism for the enantioselectivity of the allylboration of

ketones with allylboronic acids 38

541 Proposed models for enantioselectivity 40

542 Proposed catalytic cycle 41

55 Conclusions for the catalytic asymmetric allylboration 42

6 Allylboration of imines indoles and hydrazones (Paper V-VI) 43

61 Allylation of imines with allylboronic acids 43

62 Allylation of indoles with allylboronic acids 46

63 Allylation of acyl hydrazones with allylboronic acids 48

64 Mechanistic study and proposal for the allylation of aldimines 50

65 Proposed mechanism for the allylboration of hydrazones 52

66 Proposed mechanism for the allylboration of indoles 54

67 Conclusions for the allylboration of imines indoles and hydrazones 55

7 Concluding remarks 56

8 Acknowledgements 57

9 Summary in Swedish 58

10 Appendix A 59

11 References 60

x

xi

Abbreviations

Abbreviations are used in agreement with standards of the subject1 Addi-

tional non-standard or unconventional abbreviations that appear in this thesis

are listed below

B2pin2 bis(pinacolato)diboron

BINOL 11-bi-2-naphthol

Bpin pinacolato boron

BQ 14-benzoquinone

dba dibenzylideneacetone

DFT density functional theory

DMC dimethyl carbonate

dr diastereomeric ratio

er enantiomeric ratio

LA Lewis acid

L ligand (neutral)

L chiral ligand

MS molecular sieves

NOE nuclear Overhauser effect

PIFA phenyliodine bis(trifluoroacetate)

PIDA phenyliodonium diacetate

TFA trifluoroacetate

TS transition state

rt room temperature

X ligand (charged)

1

1 Introduction

The development of highly selective transformations is of fundamental

importance in modern organic chemistry Transition metal-catalysis is one of

the useful synthetic approaches to achieve this goal2 The allylation reaction

using allylboron reagents and other allyl sources is also an important ap-

proach to develop selective syntheses3

11 Palladium-catalyzed allylic CminusH acetoxylation

Transition metal-catalyzed substitution of allylic acetates and their ana-

logs is one of the most utilized and studied reactions4 An important method

to synthesize allylic acetates is Pd-catalyzed allylic CminusH functionalization5

Pioneering works by McMurry and Kocovsky6 and Aringkermark

7 have shown

that Pd(II)-catalyzed allylic acetoxylation of cyclic and acyclic olefins can

be achieved in the presence of acetic acid and benzoquinone (BQ) as oxidant

(Scheme 1) Mechanistic investigations by Baumlckvall8 and co-workers

indicated that a (π-allyl)palladium(II) intermediates are involved in the

process and that BQ serves as both oxidant and activator ligand in the

CminusOAc bond formation process

Scheme 1 Pd-catalyzed allylic CminusH acetoxylation reaction

7a

Recently the White9 and the Stahl

10 group independently reported new

methods for CminusH acetoxylation reactions using palladium catalysis The

latter group used O2 as an oxidant instead of BQ According to the mechanis-

tic studies by these authors the CminusH acetoxylation process take place via

Pd0 and Pd

II catalytic intermediates

Hypervalent iodine reagents were also employed as the principal compo-

nent in the allylic CminusH oxidation reactions5 11

For example Szaboacute and

co-workers11b

have reported the allylic CminusH acyloxylation reaction with

PhI(OAc)2 (2a) as the oxidant and source of OAc (Scheme 2) The use of a

2

palladium catalysts and hypervalent iodine reagents allowed an easy access

to allylic acetoxy and benzoyloxy compounds Based on the mechanistic

studies a PdIIPd

IV catalytic cycle was proposed when PhI(OAc)2 was used

as the oxidant

Scheme 2 Pd-catalyzed CminusH acetoxylation reaction reported by Szaboacute and co-

workers11b

In spite of the wide application of allylic CminusH acyloxylation reactions in

organic synthesis the stereoselective transformations of substituted cyclic

alkenes are limited Particularly the intermolecular diastereoselective CminusH

acyloxylation is still a challenge A new synthetic process for such a reaction

is presented in Chapter 2

12 Synthesis of allylboronates

Allylboronates are efficient reagents for regio- and stereoselective allyla-

tion of carbonyl compounds and some related functionalities3 12

Due to the

importance of allylboronates in synthetic organic chemistry there has been a

large interest in the development of new methods for the synthesis of these

reagents The classical synthetic procedures involve application of allyl-

Grignard and allyl-Li reagents13

However these methods have a limited

synthetic scope because of problems with the regioselective formation of the

allylboronates Palladium-catalyzed methods based on the substitution of allylic alcohol

derivatives have proven to be a versatile and relatively simple method to

obtain allylboronates The first process was reported by Miyaura and

co-workers14

(Scheme 3) In this process B2pin2 was used as the boron

source Although the regioselectivity of the reaction is excellent a drawback

of this process is the formation of varying amounts of homocoupling prod-

ucts

Scheme 3 Pd-catalyzed borylation of allylacetates

14

The Szaboacute group15

has expanded the substrate scope to include allylic

alcohols instead of allylic acetates (Scheme 4) It was also shown that

3

certain Pd(II) pincer complexes are more efficient than Pd(dba)2 In depth

mechanistic studies revealed that catalytic amounts of Lewis or Broslashnsted

acids are required in the reaction to activate the allylic alcohols for Pd-

catalyzed substitution16

The reaction is substantially accelerated in the pres-

ence of MeOH or other protic co-solvents

Scheme 4 Pd-catalyzed borylation of allylic alcohols

15c 15d

The Szaboacute group also developed palladium-catalyzed allylic C-H boryla-

tion methods17

These processes allowed for the synthesis of allylboronates

from readily available alkenes under oxidative conditions using BQ (1) or

the hypervalent iodonium salt

Ito Sawamura and their co-workers reported the regio- and stereoselec-

tive synthesis of allylboronates by Cu-catalyzed substitution of allyl

carbonates18

This method can also be extended to asymmetric catalysis for

the synthesis of enantioenriched allylboronates (Scheme 5)19

Scheme 5 Cu-catalyzed asymmetric borylation of allylcarbonates

19

Enantioselective synthesis of α-substituted allylboronates has been

reported by Hall and co-workers (Scheme 6)20

This method is based on

copper-catalyzed substitution of allylhalide substrates The chiral

allylboronates generated in this reaction were used for further transformation

without isolation

Scheme 6 Cu-catalyzed borylation reported by Hall and co-workers

20

Related Cu-catalyzed asymmetric synthesis of allylboronates have also

been independently reported by the groups of Hoveyda21

and McQuade22

Nickel-catalyzed stereospecific borylation of allylic acetates was developed

by Morken and co-workers23

The reaction is highly selective for the termi-

4

nal allylboronates (Scheme 7) The Morken group also developed palladi-

um-catalyzed enantioselective borylation methods for the synthesis of al-

lylboronates24

Scheme 7 Ni-catalyzed selective borylation of allylic acetates

23

Very recently Aggarwal and co-workers have reported a new method for

the preparation of enantioenriched allylboronates25

This so called ldquolithia-

tion-borylation methodrdquo involves homologation of vinyl boronates using

alkyl carbamates and butyllithium (BuLi) in the presence of (+)-sparteine

(Scheme 8)

Scheme 8 Synthesis of allylboronates by lithiation-borylation method

25b

As shown above synthesis of allylboron reagents has attracted large in-

terest in modern organic chemistry As a contribution to this field we devel-

oped a new method for the synthesis and isolation of allylboronic acids

which is presented in Chapter 3

13 Application of allylboronates in synthesis

Allylboronate reagents have been extensively used to synthesize numerous precursors for natural products and bioactive molecules

26

Addition of allylboronates to carbonyl and imine electrophiles is a well studied and documented reactions in synthetic organic chemistry

131 Stereoselective allylation of carbonyl compounds

Allylboration reactions of aldehydes have been widely applied for the ste-

reoselective synthesis of homoallylic alcohols3 After the discovery by Bub-

nov27

the reaction was further developed by Hoffmann28

Brown29

Roush30

and others Hoffmann and Brown carried out in depth mechanistic studies

which also explained the stereochemistry of the reaction Hoffman postulat-

ed that the reaction between allylboronates and aldehydes proceeds via a six-

5

membered cyclic TS similar to the Zimmerman-Traxler31

model (Scheme

9)28a 32

The high diastereoselectivity of the allylboration reaction is attributed to

an internal Lewis acid activation of the carbonyl functionality by the empty

p-orbital of boron

Scheme 9 Zimmerman-Traxler model to describe stereochemistry of allylboration

reaction

The addition of Lewis or Broslashnsted acids may accelerate the allylboration

of carbonyl compounds33

Hall and co-workers proposed that Lewis acids

coordinate to the lone pair of the boronate oxygen which renders the boron

atom more electron deficient (Scheme 10)33b 34

This mechanism for LA

and Broslashnsted acid activation was also confirmed by the DFT studies of

Houk and co-workers35

Scheme 10 Possible modes of Lewis acid activation for the allylboration

Allylboronates can also react with ketones yielding tertiary homoallylic

alcohols However the addition of allylboronates to ketones is much slower

than similar reactions with aldehydes Thus the selective allylation of

ketones with allylboronates often requires the use of catalysts36

In addition

most of the present methods for allylboration of ketones are limited to the

use of unsubstituted (parent) allylboronates or crotylboronates

132 Enantioselective allylation of carbonyl compounds

There are basically two main approaches for the asymmetric allylboration

of carbonyl compounds The first approach is the application of enantioen-

riched allylboronates performing chirality transfer and the second one is

6

asymmetric induction by using chiral catalyst One of the first asymmetric

allylboration reactions was reported by Roush and co-workers 13b 37

These

authors employed chiral auxiliaries attached to the boron atom (Scheme 11)

Diisopropyl tartrate (DIPT) proved to be a very efficient chiral auxiliary to

induce enantioselectivity

Scheme 11 Asymmetric allylation of aldehydes using chiral allylboronate

13b

A similar approach was reported by Soderquist and co-workers38

for the

asymmetric allylboration of aldehyde and ketones A bicyclic chiral auxilia-

ry on the boron atom was employed for highly diastereo- and enantioselec-

tive allylboration (Scheme 12)

Scheme 12 Diastereo-and enantioselective allylboration by chiral allylborane

38a

Enantiomerically pure TADDOL based allylboronates were developed by

Pietruszka and co-workers39

These reagents were used for chirality transfer

in allylboration of aldehydes (Scheme 13) The chiral auxiliary can be

recovered after the allylation by reduction with LiAlH4

Scheme 13 Asymmetric allylation of aldehyde using enantiopure allylboronate

39

Metal-catalyzed asymmetric synthesis of heterocyclic allylboronates was

described by Hall and co-workers40

These allylboronates were used in situ

for allylboration of aldehydes The key-step in synthesis of mefloquine was

performed using this method (Scheme 14)

7

Scheme 14 Asymmetric allylboration by cyclic allylboronates

40

Very recently Aggarwal and co-workers25b 41

reported an efficient

allylboration method using α-substituted enantioenriched allylboronates (see

also Scheme 8) The method is highly diastereo- and enantioselective In

addition the procedure is suitable for the synthesis of homoallylic alcohols

with two adjacent quaternary stereocenters (Scheme 15)

Scheme 15 Asymmetric allylation of ketone by α-substituted chiral allylboronate

25b

An alternative approach for the asymmetric allylboration of carbonyl

compounds involves the application of chiral catalysts Both Lewis and

Broslashnsted acids have been used for the asymmetric allylboration reactions

The first catalytic enantioselective allylboration reaction was reported by

Miyaura and co-workers (Scheme 16)33c

This reaction proceeded with a

high regio- and diastereoselectivity but the enantioselectivity was relatively

low

Scheme 16 Catalytic asymmetric allylboration of aldehyde

33c

Hall and co-workers42

reported a Sn-catalyzed asymmetric allylboration

reaction using allyl-Bpin as the allyl source A chiral diol was used as a lig-

and in this process which was supposed to coordinate to SnCl4 (Scheme 17)

8

Scheme 17 Tin-catalyzed asymmetric allylboration of aldehyde

42a

Asymmetric allylation of ketones was reported using chiral allylboronate

derived from BINOL compounds Chong and co-workers described the al-

lylation of ketones using 33-(CF3)2-BINOL boronate 3a (Scheme 18)43

The

reaction gave homoallylic alcohol product with a high level of enantioselec-

tivity

Scheme 18 Asymmetric allylation of ketone using BINOL-boronate

43

Catalytic methods have also been described to control both diastereo- and

enantioselectivity in the allylboration of ketones44

The first catalytic

enantioselective allylboration of ketones was developed by Shibasaki and

co-workers45

Broslashnsted acid such as BINOL derivatives44 46

was found to be

very efficient in the asymmetric allylboration reactions Schaus and

co-workers44

reported a method for asymmetric allylation of ketones using

isopropoxyboronate and catalytic amounts of Br2-BINOL 4a (Scheme 19)

Scheme 19 Catalytic asymmetric allylboration of ketone using Br2-BINOL

44a

These authors proposed a Zimmerman-Traxler type transition state to

rationalize the enantioselectivity in this reaction It has been also pointed out

that the substituent in BINOL (eg Br or CF3) has an important role for the

enantioselectivity of these reactions

Catalytic synthesis of homoallylic alcohols containing adjacent quater-

nary stereocenters has been a great challenge in synthetic organic chemistry

A new synthetic method for such reaction is presented in Section 52

9

133 Stereoselective allylation of imines

Homoallylic amine motifs occur in many natural products and biological-

ly relevant compounds47

One of the most common strategies for homoallylic

amine synthesis is the addition of allyl-metal reagents to imines48

The use of

allylboronate compounds for these reactions has emerged as an important

synthetic approach47

Allylboronates have a low toxicity high functional

group tolerance and the allylation of imines occurs with a high level of

selectivity

Stereoselective allylation of aldimines can be performed by

allylboronates in the presence of Lewis acid catalysts Batey and

co-workers49

reported the allylboration of N-toluenesulfonylimines using

crotyltrifluroboronate and BF3OEt2 (Scheme 20) The allylation was

proposed to proceed via the allyl-BF2 species which is generated from

allyl-BF3K

Scheme 20 Stereoselective allylation of imine by allyltrifluoroborate

49

Kobayashi and co-workers50

reported a three-component diastereoselec-

tive allylation reaction to synthesize homoallylic primary amines (Scheme

21) In addition several useful methods for asymmetric allylboration of

imines25b 51

using allylboronates can also be found in literature

Scheme 21 Synthesis of homoallylic amine using multicomponent method

50

Allylboration of acylhydrazones have also proven to be a very useful

reaction for the synthesis of homoallylic amine derivatives However the

allylation of acylhydrazones by allylboronates requires the application of

metal catalysts52

An indium-catalyzed reaction for the allylation of N-

acylhydrazone was reported by Kobayashi and co-workers (Scheme 22)52a

It

has been proposed that indium undergoes a transmetallation with allyl-Bpin

to form an active allyl-indium species which then added to the hydrazone

10

Scheme 22 Indium-catalyzed allylation of acylhydrazone

52a

We have developed a stereoselective method for allylation of imines and

acylhydrazones using allylboronic acids These results are summarized in

Chapter 6

11

2 Pd-catalyzed stereoselective allylic CminusH

trifluoroacetoxylation (Paper I)

As mentioned in the introduction transition metal-catalyzed CminusH bond activation methods have attracted increasing interest in organic synthesis

53

Using these methods multistep synthesis for prefunctionalization of the or-ganic substrates is not necessary In addition the waste production of the reaction can be reduced as the new functional group can be installed by re-placement of hydrogen

54 Palladium-catalyzed allylic CminusH bond activation is

one of the oldest and most versatile CminusH functionalization method (Section 11)

55 In this reaction (as in CminusH activation based processes in general) the

greatest challenge is the control of the regio- and stereoselectivity of the process

Stereodefined allylic acetates are very important precursors for regio- and stereoselective palladium-catalyzed allylic substitution reactions

56 Although

many regioselective allylic CminusH functionalization methods have been re-ported there are few reports on stereoselective allylic CminusH acetoxylation

7a

Most of these studies are intramolecular CminusH acyloxylation reactions For example a stereoselective allylic CminusH acetoxylation method has been re-ported by White and co-workers (Scheme 23) Intramolecular selectivity control allowed macrocyclization

57 and straightforward synthesis of anti-14-

dioxan-2-ones58

from simple olefins using Pd(II)sulfoxide catalysis Baumlck-vall and co-workers

59 have also developed several methods for the synthesis

of allylacetoxy compounds based on palladium-catalyzed intramolecular oxidative carbocyclization

Scheme 23 Stereoselective intramolecular CminusH oxidation reported by White and

co-workers58

12

21 Development of selective intermolecular allylic CminusH trifluoroacetoxylation

As our group previously developed a useful allylic CminusH acetoxylation

method based on using PhI(OAc)2 (2a) (see Section 11) as oxidant and ace-

tate source we envisioned that PhI(OCOCF3)2 (2b) can also be used in this

type of reaction to introduce a trifluoroacetate group at the allylic position of

alkenes Allylic trifluoroacetates are more reactive than allylic acetates in

transition metal-catalyzed substitutions60

and therefore an easy access to

these compounds is desirable As far as we know selective allylic CminusH tri-

fluoroacetoxylation has not been reported in the literature

In the early stage of development and optimization we employed car-

boxylated alkene 6a as our model substrate as it gave a high yield and ex-

hibited high selectivity in the Pd-catalyzed CminusH acetoxylation with 2a11b

However PhI(OCOCF3)2 (2b) is most likely a stronger oxidant than

PhI(OAc)2 (2a) and therefore we could not use oxidation sensitive solvents

such as THF or DMSO In addition the conjugated acid of the trifluoroace-

tate ion (the nucleophile) is a strong acid and therefore trifluoroacetic acid

could not be used as the solvent either After short optimization we have

found that dimethyl carbonate (DMC) is an excellent solvent for all reaction

components and it is not oxidized by PIFA We have found that the isolated

yields are higher when LiOCOCF3 is used as additive Under these condi-

tions the reaction could be performed with various functionalized alkenes

(Table 1)

13

Table 1 Pd-catalyzed allylic CminusH trifluoroacetoxylation of acyclic olefinsa

Both Pd(OAc)2 (5b) and Pd(OCOCF3)2 (5c) were equally efficient as cat-

alyst in the reaction So we decided to use 5b in the present synthetic method

as it is less expensive than 5c Not only terminal (6a) but internal alkenes

6b-c could also be used for trifluoroacetoxylation with high selectivity Oth-

er alkenes with electron withdrawing substituents such as 6d-e could also be

smoothly trifluoroacetoxylated Substrates without electron-withdrawing

groups gave intractable mixtures of trifluoroacetoxylated products For com-

pounds with long alkyl chain oxidation of the double bond occurred while in

the case of electron donating substituents mainly oxidation of the double

bond occurred together with other processes

14

Table 2 Stereoselective allylic CminusH trifluoroacetoxylation of cyclic alkenesa

Not only acyclic alkenes but cyclic alkenes could also be employed for

the trifluoroacetoxylation reaction Monosubstituted cyclic alkenes reacted

with a remarkably high selectivity (Table 2) The reaction conditions were

very similar to the trifluoroacetoxylation of acyclic substrates (Table 1) but

in order to get this high stereoselectivity the reactions had to be conducted

at 0 degC This is below the freezing point of DMC therefore the reaction me-

dium was diluted with DCM to avoid freezing of the reaction mixture The

yields with LiOCOCF3 were as high as in its absence therefore we did not

use this additive in the trifluoroacetoxylation of cyclic substrates

Considering the number of possible regio- and stereoisomers a mixture

of six allylic trifluoroacetate products could be expected Yet in most cases

we obtained a single diastereomer with very high regioselectivity (Table 2

entries 1-2 and 4-5) The major regioisomer in all cases was the 14-

substituted product (7f-j) with anti diastereoselectivity and the minor prod-

uct is the regioisomer of the same diastereomer The stereochemistry of the

major isomers was assigned based on NOE experiments

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

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1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

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1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

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34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

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83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

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88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

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94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

v

Abstract

This thesis is focused on two main areas of organic synthesis palladium-

catalyzed functionalization of alkenes and allylic alcohols as well as devel-

opment of new allylboration reactions

We have developed a palladium-catalyzed selective allylic trifluoroace-

toxylation reaction based on CminusH functionalization Allylic trifluoroacetates

were synthesized from functionalized olefins under oxidative conditions

The reactions proceed under mild conditions with a high level of diastereose-

lectivity Mechanistic studies of the allylic CminusH trifluoroacetoxylation

indicate that the reaction proceeds via (η3-allyl)palladium(IV) intermediate

Palladium-catalyzed regio- and stereoselective synthesis of allylboronic

acids from allylic alcohols has been demonstrated Diboronic acid B2(OH)4

was used as the boron source in this process

The reactivity of the allylboronic acids were studied in three types of

allylboration reactions allylboration of ketones imines and acyl hydrazones

All three processes are conducted under mild conditions without any

additives The reactions proceeded with remarkably high regio- and stereose-

lectivity

An asymmetric version of the allylboration of ketones was also devel-

oped In this process chiral BINOL derivatives were used as catalysts The

reaction using γ-disubstituted allylboronic acids and various aromatic and

aliphatic ketones afforded homoallylic alcohols bearing two adjacent quater-

nary stereocenters with excellent regio- diastereo- and enantioselectivity (up

to 973 er) in high yield The stereoselectivity in the allylboration reactions

could be rationalized on the basis of the Zimmerman-Traxler TS model

vi

vii

List of Publications

This thesis is based on a licentiate thesis by Rauful Alam entitled ldquoPalladi-

um-catalyzed Allylic CminusH and CminusOH Functionalization Reactions of the

Obtained Allylboronic Acidsrdquo and the following papers referred to in text

by their Roman numerals I-VI Reprints were made with the kind permission

from the publishers (Appendix A)

I Stereoselective Intermolecular Allylic C-H Trifluoroacetoxylation

of Functionalized Alkenes

Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

II Palladium-Catalyzed Synthesis and Isolation of Functionalized

Allylboronic Acids Facile Direct Allylboration of Ketones Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

III Selective Formation of Adjacent Stereocenters by Allylboration of

Ketones under Mild Neutral Conditions Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

IV Synthesis of Adjacent Quaternary Stereocenters by Catalytic

Asymmetric Allylboration

Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

V Stereoselective Allylboration of Imines and Indoles under Mild

Conditions An in situ EZ Isomerization of Imines by Allylborox-

ines Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

VI Stereocontrol in Synthesis of Homoallylic Amines Syn Selective

Direct Allylation of Hydrazones with Allylboronic Acids Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

viii

Contents

Abstract v

List of Publications vii

Contents viii

Abbreviations xi

1 Introduction 1

11 Palladium-catalyzed allylic CminusH acetoxylation 1

12 Synthesis of allylboronates 2

13 Application of allylboronates in synthesis 4

131 Stereoselective allylation of carbonyl compounds 4

132 Enantioselective allylation of carbonyl compounds 5

133 Stereoselective allylation of imines 9

2 Pd-catalyzed stereoselective allylic CminusH trifluoroacetoxylation (Paper I) 11

21 Development of selective intermolecular allylic CminusH

trifluoroacetoxylationhelliphelliphelliphellip 12

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation 15

23 Conclusions for the allylic CminusH trifluoroacetoxylation 17

3 Pd-catalyzed synthesis and isolation of allylboronic acids (Paper II) 18

31 Development of new synthetic methods for the synthesis and isolation of

allylboronic acids 18

311 Diboronic acid B2(OH)4 as boron source 19

312 Synthesis of allylboronic acids and their isolation 20

32 Characterization of allylboroxine 22

33 Proposed mechanism for the allylic CminusOH borylation 24

34 Conclusions for the allylic CminusOH borylation 25

4 Allylboration of carbonyl compounds using allylboronic acids (Paper II-III) 26

41 Allylation of ketones by allylboronic acids 26

42 Stereoselectivity of α-hydroxy acids 31

43 Conclusions for allylboration of carbonyl compounds 32

ix

5 Synthesis of adjacent quaternary stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV) 33

51 Method development for the asymmetric allylboration of ketones helliphellip33

52 Stereocontrol in the asymmetric allylboration of ketone 35

53 Catalytic enantioselective allylboration of ketones 36

54 Proposed mechanism for the enantioselectivity of the allylboration of

ketones with allylboronic acids 38

541 Proposed models for enantioselectivity 40

542 Proposed catalytic cycle 41

55 Conclusions for the catalytic asymmetric allylboration 42

6 Allylboration of imines indoles and hydrazones (Paper V-VI) 43

61 Allylation of imines with allylboronic acids 43

62 Allylation of indoles with allylboronic acids 46

63 Allylation of acyl hydrazones with allylboronic acids 48

64 Mechanistic study and proposal for the allylation of aldimines 50

65 Proposed mechanism for the allylboration of hydrazones 52

66 Proposed mechanism for the allylboration of indoles 54

67 Conclusions for the allylboration of imines indoles and hydrazones 55

7 Concluding remarks 56

8 Acknowledgements 57

9 Summary in Swedish 58

10 Appendix A 59

11 References 60

x

xi

Abbreviations

Abbreviations are used in agreement with standards of the subject1 Addi-

tional non-standard or unconventional abbreviations that appear in this thesis

are listed below

B2pin2 bis(pinacolato)diboron

BINOL 11-bi-2-naphthol

Bpin pinacolato boron

BQ 14-benzoquinone

dba dibenzylideneacetone

DFT density functional theory

DMC dimethyl carbonate

dr diastereomeric ratio

er enantiomeric ratio

LA Lewis acid

L ligand (neutral)

L chiral ligand

MS molecular sieves

NOE nuclear Overhauser effect

PIFA phenyliodine bis(trifluoroacetate)

PIDA phenyliodonium diacetate

TFA trifluoroacetate

TS transition state

rt room temperature

X ligand (charged)

1

1 Introduction

The development of highly selective transformations is of fundamental

importance in modern organic chemistry Transition metal-catalysis is one of

the useful synthetic approaches to achieve this goal2 The allylation reaction

using allylboron reagents and other allyl sources is also an important ap-

proach to develop selective syntheses3

11 Palladium-catalyzed allylic CminusH acetoxylation

Transition metal-catalyzed substitution of allylic acetates and their ana-

logs is one of the most utilized and studied reactions4 An important method

to synthesize allylic acetates is Pd-catalyzed allylic CminusH functionalization5

Pioneering works by McMurry and Kocovsky6 and Aringkermark

7 have shown

that Pd(II)-catalyzed allylic acetoxylation of cyclic and acyclic olefins can

be achieved in the presence of acetic acid and benzoquinone (BQ) as oxidant

(Scheme 1) Mechanistic investigations by Baumlckvall8 and co-workers

indicated that a (π-allyl)palladium(II) intermediates are involved in the

process and that BQ serves as both oxidant and activator ligand in the

CminusOAc bond formation process

Scheme 1 Pd-catalyzed allylic CminusH acetoxylation reaction

7a

Recently the White9 and the Stahl

10 group independently reported new

methods for CminusH acetoxylation reactions using palladium catalysis The

latter group used O2 as an oxidant instead of BQ According to the mechanis-

tic studies by these authors the CminusH acetoxylation process take place via

Pd0 and Pd

II catalytic intermediates

Hypervalent iodine reagents were also employed as the principal compo-

nent in the allylic CminusH oxidation reactions5 11

For example Szaboacute and

co-workers11b

have reported the allylic CminusH acyloxylation reaction with

PhI(OAc)2 (2a) as the oxidant and source of OAc (Scheme 2) The use of a

2

palladium catalysts and hypervalent iodine reagents allowed an easy access

to allylic acetoxy and benzoyloxy compounds Based on the mechanistic

studies a PdIIPd

IV catalytic cycle was proposed when PhI(OAc)2 was used

as the oxidant

Scheme 2 Pd-catalyzed CminusH acetoxylation reaction reported by Szaboacute and co-

workers11b

In spite of the wide application of allylic CminusH acyloxylation reactions in

organic synthesis the stereoselective transformations of substituted cyclic

alkenes are limited Particularly the intermolecular diastereoselective CminusH

acyloxylation is still a challenge A new synthetic process for such a reaction

is presented in Chapter 2

12 Synthesis of allylboronates

Allylboronates are efficient reagents for regio- and stereoselective allyla-

tion of carbonyl compounds and some related functionalities3 12

Due to the

importance of allylboronates in synthetic organic chemistry there has been a

large interest in the development of new methods for the synthesis of these

reagents The classical synthetic procedures involve application of allyl-

Grignard and allyl-Li reagents13

However these methods have a limited

synthetic scope because of problems with the regioselective formation of the

allylboronates Palladium-catalyzed methods based on the substitution of allylic alcohol

derivatives have proven to be a versatile and relatively simple method to

obtain allylboronates The first process was reported by Miyaura and

co-workers14

(Scheme 3) In this process B2pin2 was used as the boron

source Although the regioselectivity of the reaction is excellent a drawback

of this process is the formation of varying amounts of homocoupling prod-

ucts

Scheme 3 Pd-catalyzed borylation of allylacetates

14

The Szaboacute group15

has expanded the substrate scope to include allylic

alcohols instead of allylic acetates (Scheme 4) It was also shown that

3

certain Pd(II) pincer complexes are more efficient than Pd(dba)2 In depth

mechanistic studies revealed that catalytic amounts of Lewis or Broslashnsted

acids are required in the reaction to activate the allylic alcohols for Pd-

catalyzed substitution16

The reaction is substantially accelerated in the pres-

ence of MeOH or other protic co-solvents

Scheme 4 Pd-catalyzed borylation of allylic alcohols

15c 15d

The Szaboacute group also developed palladium-catalyzed allylic C-H boryla-

tion methods17

These processes allowed for the synthesis of allylboronates

from readily available alkenes under oxidative conditions using BQ (1) or

the hypervalent iodonium salt

Ito Sawamura and their co-workers reported the regio- and stereoselec-

tive synthesis of allylboronates by Cu-catalyzed substitution of allyl

carbonates18

This method can also be extended to asymmetric catalysis for

the synthesis of enantioenriched allylboronates (Scheme 5)19

Scheme 5 Cu-catalyzed asymmetric borylation of allylcarbonates

19

Enantioselective synthesis of α-substituted allylboronates has been

reported by Hall and co-workers (Scheme 6)20

This method is based on

copper-catalyzed substitution of allylhalide substrates The chiral

allylboronates generated in this reaction were used for further transformation

without isolation

Scheme 6 Cu-catalyzed borylation reported by Hall and co-workers

20

Related Cu-catalyzed asymmetric synthesis of allylboronates have also

been independently reported by the groups of Hoveyda21

and McQuade22

Nickel-catalyzed stereospecific borylation of allylic acetates was developed

by Morken and co-workers23

The reaction is highly selective for the termi-

4

nal allylboronates (Scheme 7) The Morken group also developed palladi-

um-catalyzed enantioselective borylation methods for the synthesis of al-

lylboronates24

Scheme 7 Ni-catalyzed selective borylation of allylic acetates

23

Very recently Aggarwal and co-workers have reported a new method for

the preparation of enantioenriched allylboronates25

This so called ldquolithia-

tion-borylation methodrdquo involves homologation of vinyl boronates using

alkyl carbamates and butyllithium (BuLi) in the presence of (+)-sparteine

(Scheme 8)

Scheme 8 Synthesis of allylboronates by lithiation-borylation method

25b

As shown above synthesis of allylboron reagents has attracted large in-

terest in modern organic chemistry As a contribution to this field we devel-

oped a new method for the synthesis and isolation of allylboronic acids

which is presented in Chapter 3

13 Application of allylboronates in synthesis

Allylboronate reagents have been extensively used to synthesize numerous precursors for natural products and bioactive molecules

26

Addition of allylboronates to carbonyl and imine electrophiles is a well studied and documented reactions in synthetic organic chemistry

131 Stereoselective allylation of carbonyl compounds

Allylboration reactions of aldehydes have been widely applied for the ste-

reoselective synthesis of homoallylic alcohols3 After the discovery by Bub-

nov27

the reaction was further developed by Hoffmann28

Brown29

Roush30

and others Hoffmann and Brown carried out in depth mechanistic studies

which also explained the stereochemistry of the reaction Hoffman postulat-

ed that the reaction between allylboronates and aldehydes proceeds via a six-

5

membered cyclic TS similar to the Zimmerman-Traxler31

model (Scheme

9)28a 32

The high diastereoselectivity of the allylboration reaction is attributed to

an internal Lewis acid activation of the carbonyl functionality by the empty

p-orbital of boron

Scheme 9 Zimmerman-Traxler model to describe stereochemistry of allylboration

reaction

The addition of Lewis or Broslashnsted acids may accelerate the allylboration

of carbonyl compounds33

Hall and co-workers proposed that Lewis acids

coordinate to the lone pair of the boronate oxygen which renders the boron

atom more electron deficient (Scheme 10)33b 34

This mechanism for LA

and Broslashnsted acid activation was also confirmed by the DFT studies of

Houk and co-workers35

Scheme 10 Possible modes of Lewis acid activation for the allylboration

Allylboronates can also react with ketones yielding tertiary homoallylic

alcohols However the addition of allylboronates to ketones is much slower

than similar reactions with aldehydes Thus the selective allylation of

ketones with allylboronates often requires the use of catalysts36

In addition

most of the present methods for allylboration of ketones are limited to the

use of unsubstituted (parent) allylboronates or crotylboronates

132 Enantioselective allylation of carbonyl compounds

There are basically two main approaches for the asymmetric allylboration

of carbonyl compounds The first approach is the application of enantioen-

riched allylboronates performing chirality transfer and the second one is

6

asymmetric induction by using chiral catalyst One of the first asymmetric

allylboration reactions was reported by Roush and co-workers 13b 37

These

authors employed chiral auxiliaries attached to the boron atom (Scheme 11)

Diisopropyl tartrate (DIPT) proved to be a very efficient chiral auxiliary to

induce enantioselectivity

Scheme 11 Asymmetric allylation of aldehydes using chiral allylboronate

13b

A similar approach was reported by Soderquist and co-workers38

for the

asymmetric allylboration of aldehyde and ketones A bicyclic chiral auxilia-

ry on the boron atom was employed for highly diastereo- and enantioselec-

tive allylboration (Scheme 12)

Scheme 12 Diastereo-and enantioselective allylboration by chiral allylborane

38a

Enantiomerically pure TADDOL based allylboronates were developed by

Pietruszka and co-workers39

These reagents were used for chirality transfer

in allylboration of aldehydes (Scheme 13) The chiral auxiliary can be

recovered after the allylation by reduction with LiAlH4

Scheme 13 Asymmetric allylation of aldehyde using enantiopure allylboronate

39

Metal-catalyzed asymmetric synthesis of heterocyclic allylboronates was

described by Hall and co-workers40

These allylboronates were used in situ

for allylboration of aldehydes The key-step in synthesis of mefloquine was

performed using this method (Scheme 14)

7

Scheme 14 Asymmetric allylboration by cyclic allylboronates

40

Very recently Aggarwal and co-workers25b 41

reported an efficient

allylboration method using α-substituted enantioenriched allylboronates (see

also Scheme 8) The method is highly diastereo- and enantioselective In

addition the procedure is suitable for the synthesis of homoallylic alcohols

with two adjacent quaternary stereocenters (Scheme 15)

Scheme 15 Asymmetric allylation of ketone by α-substituted chiral allylboronate

25b

An alternative approach for the asymmetric allylboration of carbonyl

compounds involves the application of chiral catalysts Both Lewis and

Broslashnsted acids have been used for the asymmetric allylboration reactions

The first catalytic enantioselective allylboration reaction was reported by

Miyaura and co-workers (Scheme 16)33c

This reaction proceeded with a

high regio- and diastereoselectivity but the enantioselectivity was relatively

low

Scheme 16 Catalytic asymmetric allylboration of aldehyde

33c

Hall and co-workers42

reported a Sn-catalyzed asymmetric allylboration

reaction using allyl-Bpin as the allyl source A chiral diol was used as a lig-

and in this process which was supposed to coordinate to SnCl4 (Scheme 17)

8

Scheme 17 Tin-catalyzed asymmetric allylboration of aldehyde

42a

Asymmetric allylation of ketones was reported using chiral allylboronate

derived from BINOL compounds Chong and co-workers described the al-

lylation of ketones using 33-(CF3)2-BINOL boronate 3a (Scheme 18)43

The

reaction gave homoallylic alcohol product with a high level of enantioselec-

tivity

Scheme 18 Asymmetric allylation of ketone using BINOL-boronate

43

Catalytic methods have also been described to control both diastereo- and

enantioselectivity in the allylboration of ketones44

The first catalytic

enantioselective allylboration of ketones was developed by Shibasaki and

co-workers45

Broslashnsted acid such as BINOL derivatives44 46

was found to be

very efficient in the asymmetric allylboration reactions Schaus and

co-workers44

reported a method for asymmetric allylation of ketones using

isopropoxyboronate and catalytic amounts of Br2-BINOL 4a (Scheme 19)

Scheme 19 Catalytic asymmetric allylboration of ketone using Br2-BINOL

44a

These authors proposed a Zimmerman-Traxler type transition state to

rationalize the enantioselectivity in this reaction It has been also pointed out

that the substituent in BINOL (eg Br or CF3) has an important role for the

enantioselectivity of these reactions

Catalytic synthesis of homoallylic alcohols containing adjacent quater-

nary stereocenters has been a great challenge in synthetic organic chemistry

A new synthetic method for such reaction is presented in Section 52

9

133 Stereoselective allylation of imines

Homoallylic amine motifs occur in many natural products and biological-

ly relevant compounds47

One of the most common strategies for homoallylic

amine synthesis is the addition of allyl-metal reagents to imines48

The use of

allylboronate compounds for these reactions has emerged as an important

synthetic approach47

Allylboronates have a low toxicity high functional

group tolerance and the allylation of imines occurs with a high level of

selectivity

Stereoselective allylation of aldimines can be performed by

allylboronates in the presence of Lewis acid catalysts Batey and

co-workers49

reported the allylboration of N-toluenesulfonylimines using

crotyltrifluroboronate and BF3OEt2 (Scheme 20) The allylation was

proposed to proceed via the allyl-BF2 species which is generated from

allyl-BF3K

Scheme 20 Stereoselective allylation of imine by allyltrifluoroborate

49

Kobayashi and co-workers50

reported a three-component diastereoselec-

tive allylation reaction to synthesize homoallylic primary amines (Scheme

21) In addition several useful methods for asymmetric allylboration of

imines25b 51

using allylboronates can also be found in literature

Scheme 21 Synthesis of homoallylic amine using multicomponent method

50

Allylboration of acylhydrazones have also proven to be a very useful

reaction for the synthesis of homoallylic amine derivatives However the

allylation of acylhydrazones by allylboronates requires the application of

metal catalysts52

An indium-catalyzed reaction for the allylation of N-

acylhydrazone was reported by Kobayashi and co-workers (Scheme 22)52a

It

has been proposed that indium undergoes a transmetallation with allyl-Bpin

to form an active allyl-indium species which then added to the hydrazone

10

Scheme 22 Indium-catalyzed allylation of acylhydrazone

52a

We have developed a stereoselective method for allylation of imines and

acylhydrazones using allylboronic acids These results are summarized in

Chapter 6

11

2 Pd-catalyzed stereoselective allylic CminusH

trifluoroacetoxylation (Paper I)

As mentioned in the introduction transition metal-catalyzed CminusH bond activation methods have attracted increasing interest in organic synthesis

53

Using these methods multistep synthesis for prefunctionalization of the or-ganic substrates is not necessary In addition the waste production of the reaction can be reduced as the new functional group can be installed by re-placement of hydrogen

54 Palladium-catalyzed allylic CminusH bond activation is

one of the oldest and most versatile CminusH functionalization method (Section 11)

55 In this reaction (as in CminusH activation based processes in general) the

greatest challenge is the control of the regio- and stereoselectivity of the process

Stereodefined allylic acetates are very important precursors for regio- and stereoselective palladium-catalyzed allylic substitution reactions

56 Although

many regioselective allylic CminusH functionalization methods have been re-ported there are few reports on stereoselective allylic CminusH acetoxylation

7a

Most of these studies are intramolecular CminusH acyloxylation reactions For example a stereoselective allylic CminusH acetoxylation method has been re-ported by White and co-workers (Scheme 23) Intramolecular selectivity control allowed macrocyclization

57 and straightforward synthesis of anti-14-

dioxan-2-ones58

from simple olefins using Pd(II)sulfoxide catalysis Baumlck-vall and co-workers

59 have also developed several methods for the synthesis

of allylacetoxy compounds based on palladium-catalyzed intramolecular oxidative carbocyclization

Scheme 23 Stereoselective intramolecular CminusH oxidation reported by White and

co-workers58

12

21 Development of selective intermolecular allylic CminusH trifluoroacetoxylation

As our group previously developed a useful allylic CminusH acetoxylation

method based on using PhI(OAc)2 (2a) (see Section 11) as oxidant and ace-

tate source we envisioned that PhI(OCOCF3)2 (2b) can also be used in this

type of reaction to introduce a trifluoroacetate group at the allylic position of

alkenes Allylic trifluoroacetates are more reactive than allylic acetates in

transition metal-catalyzed substitutions60

and therefore an easy access to

these compounds is desirable As far as we know selective allylic CminusH tri-

fluoroacetoxylation has not been reported in the literature

In the early stage of development and optimization we employed car-

boxylated alkene 6a as our model substrate as it gave a high yield and ex-

hibited high selectivity in the Pd-catalyzed CminusH acetoxylation with 2a11b

However PhI(OCOCF3)2 (2b) is most likely a stronger oxidant than

PhI(OAc)2 (2a) and therefore we could not use oxidation sensitive solvents

such as THF or DMSO In addition the conjugated acid of the trifluoroace-

tate ion (the nucleophile) is a strong acid and therefore trifluoroacetic acid

could not be used as the solvent either After short optimization we have

found that dimethyl carbonate (DMC) is an excellent solvent for all reaction

components and it is not oxidized by PIFA We have found that the isolated

yields are higher when LiOCOCF3 is used as additive Under these condi-

tions the reaction could be performed with various functionalized alkenes

(Table 1)

13

Table 1 Pd-catalyzed allylic CminusH trifluoroacetoxylation of acyclic olefinsa

Both Pd(OAc)2 (5b) and Pd(OCOCF3)2 (5c) were equally efficient as cat-

alyst in the reaction So we decided to use 5b in the present synthetic method

as it is less expensive than 5c Not only terminal (6a) but internal alkenes

6b-c could also be used for trifluoroacetoxylation with high selectivity Oth-

er alkenes with electron withdrawing substituents such as 6d-e could also be

smoothly trifluoroacetoxylated Substrates without electron-withdrawing

groups gave intractable mixtures of trifluoroacetoxylated products For com-

pounds with long alkyl chain oxidation of the double bond occurred while in

the case of electron donating substituents mainly oxidation of the double

bond occurred together with other processes

14

Table 2 Stereoselective allylic CminusH trifluoroacetoxylation of cyclic alkenesa

Not only acyclic alkenes but cyclic alkenes could also be employed for

the trifluoroacetoxylation reaction Monosubstituted cyclic alkenes reacted

with a remarkably high selectivity (Table 2) The reaction conditions were

very similar to the trifluoroacetoxylation of acyclic substrates (Table 1) but

in order to get this high stereoselectivity the reactions had to be conducted

at 0 degC This is below the freezing point of DMC therefore the reaction me-

dium was diluted with DCM to avoid freezing of the reaction mixture The

yields with LiOCOCF3 were as high as in its absence therefore we did not

use this additive in the trifluoroacetoxylation of cyclic substrates

Considering the number of possible regio- and stereoisomers a mixture

of six allylic trifluoroacetate products could be expected Yet in most cases

we obtained a single diastereomer with very high regioselectivity (Table 2

entries 1-2 and 4-5) The major regioisomer in all cases was the 14-

substituted product (7f-j) with anti diastereoselectivity and the minor prod-

uct is the regioisomer of the same diastereomer The stereochemistry of the

major isomers was assigned based on NOE experiments

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

1 The ACS Style Guide 3rd ed Oxford University Press New York 2006

2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

vi

vii

List of Publications

This thesis is based on a licentiate thesis by Rauful Alam entitled ldquoPalladi-

um-catalyzed Allylic CminusH and CminusOH Functionalization Reactions of the

Obtained Allylboronic Acidsrdquo and the following papers referred to in text

by their Roman numerals I-VI Reprints were made with the kind permission

from the publishers (Appendix A)

I Stereoselective Intermolecular Allylic C-H Trifluoroacetoxylation

of Functionalized Alkenes

Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

II Palladium-Catalyzed Synthesis and Isolation of Functionalized

Allylboronic Acids Facile Direct Allylboration of Ketones Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

III Selective Formation of Adjacent Stereocenters by Allylboration of

Ketones under Mild Neutral Conditions Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

IV Synthesis of Adjacent Quaternary Stereocenters by Catalytic

Asymmetric Allylboration

Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

V Stereoselective Allylboration of Imines and Indoles under Mild

Conditions An in situ EZ Isomerization of Imines by Allylborox-

ines Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

VI Stereocontrol in Synthesis of Homoallylic Amines Syn Selective

Direct Allylation of Hydrazones with Allylboronic Acids Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

viii

Contents

Abstract v

List of Publications vii

Contents viii

Abbreviations xi

1 Introduction 1

11 Palladium-catalyzed allylic CminusH acetoxylation 1

12 Synthesis of allylboronates 2

13 Application of allylboronates in synthesis 4

131 Stereoselective allylation of carbonyl compounds 4

132 Enantioselective allylation of carbonyl compounds 5

133 Stereoselective allylation of imines 9

2 Pd-catalyzed stereoselective allylic CminusH trifluoroacetoxylation (Paper I) 11

21 Development of selective intermolecular allylic CminusH

trifluoroacetoxylationhelliphelliphelliphellip 12

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation 15

23 Conclusions for the allylic CminusH trifluoroacetoxylation 17

3 Pd-catalyzed synthesis and isolation of allylboronic acids (Paper II) 18

31 Development of new synthetic methods for the synthesis and isolation of

allylboronic acids 18

311 Diboronic acid B2(OH)4 as boron source 19

312 Synthesis of allylboronic acids and their isolation 20

32 Characterization of allylboroxine 22

33 Proposed mechanism for the allylic CminusOH borylation 24

34 Conclusions for the allylic CminusOH borylation 25

4 Allylboration of carbonyl compounds using allylboronic acids (Paper II-III) 26

41 Allylation of ketones by allylboronic acids 26

42 Stereoselectivity of α-hydroxy acids 31

43 Conclusions for allylboration of carbonyl compounds 32

ix

5 Synthesis of adjacent quaternary stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV) 33

51 Method development for the asymmetric allylboration of ketones helliphellip33

52 Stereocontrol in the asymmetric allylboration of ketone 35

53 Catalytic enantioselective allylboration of ketones 36

54 Proposed mechanism for the enantioselectivity of the allylboration of

ketones with allylboronic acids 38

541 Proposed models for enantioselectivity 40

542 Proposed catalytic cycle 41

55 Conclusions for the catalytic asymmetric allylboration 42

6 Allylboration of imines indoles and hydrazones (Paper V-VI) 43

61 Allylation of imines with allylboronic acids 43

62 Allylation of indoles with allylboronic acids 46

63 Allylation of acyl hydrazones with allylboronic acids 48

64 Mechanistic study and proposal for the allylation of aldimines 50

65 Proposed mechanism for the allylboration of hydrazones 52

66 Proposed mechanism for the allylboration of indoles 54

67 Conclusions for the allylboration of imines indoles and hydrazones 55

7 Concluding remarks 56

8 Acknowledgements 57

9 Summary in Swedish 58

10 Appendix A 59

11 References 60

x

xi

Abbreviations

Abbreviations are used in agreement with standards of the subject1 Addi-

tional non-standard or unconventional abbreviations that appear in this thesis

are listed below

B2pin2 bis(pinacolato)diboron

BINOL 11-bi-2-naphthol

Bpin pinacolato boron

BQ 14-benzoquinone

dba dibenzylideneacetone

DFT density functional theory

DMC dimethyl carbonate

dr diastereomeric ratio

er enantiomeric ratio

LA Lewis acid

L ligand (neutral)

L chiral ligand

MS molecular sieves

NOE nuclear Overhauser effect

PIFA phenyliodine bis(trifluoroacetate)

PIDA phenyliodonium diacetate

TFA trifluoroacetate

TS transition state

rt room temperature

X ligand (charged)

1

1 Introduction

The development of highly selective transformations is of fundamental

importance in modern organic chemistry Transition metal-catalysis is one of

the useful synthetic approaches to achieve this goal2 The allylation reaction

using allylboron reagents and other allyl sources is also an important ap-

proach to develop selective syntheses3

11 Palladium-catalyzed allylic CminusH acetoxylation

Transition metal-catalyzed substitution of allylic acetates and their ana-

logs is one of the most utilized and studied reactions4 An important method

to synthesize allylic acetates is Pd-catalyzed allylic CminusH functionalization5

Pioneering works by McMurry and Kocovsky6 and Aringkermark

7 have shown

that Pd(II)-catalyzed allylic acetoxylation of cyclic and acyclic olefins can

be achieved in the presence of acetic acid and benzoquinone (BQ) as oxidant

(Scheme 1) Mechanistic investigations by Baumlckvall8 and co-workers

indicated that a (π-allyl)palladium(II) intermediates are involved in the

process and that BQ serves as both oxidant and activator ligand in the

CminusOAc bond formation process

Scheme 1 Pd-catalyzed allylic CminusH acetoxylation reaction

7a

Recently the White9 and the Stahl

10 group independently reported new

methods for CminusH acetoxylation reactions using palladium catalysis The

latter group used O2 as an oxidant instead of BQ According to the mechanis-

tic studies by these authors the CminusH acetoxylation process take place via

Pd0 and Pd

II catalytic intermediates

Hypervalent iodine reagents were also employed as the principal compo-

nent in the allylic CminusH oxidation reactions5 11

For example Szaboacute and

co-workers11b

have reported the allylic CminusH acyloxylation reaction with

PhI(OAc)2 (2a) as the oxidant and source of OAc (Scheme 2) The use of a

2

palladium catalysts and hypervalent iodine reagents allowed an easy access

to allylic acetoxy and benzoyloxy compounds Based on the mechanistic

studies a PdIIPd

IV catalytic cycle was proposed when PhI(OAc)2 was used

as the oxidant

Scheme 2 Pd-catalyzed CminusH acetoxylation reaction reported by Szaboacute and co-

workers11b

In spite of the wide application of allylic CminusH acyloxylation reactions in

organic synthesis the stereoselective transformations of substituted cyclic

alkenes are limited Particularly the intermolecular diastereoselective CminusH

acyloxylation is still a challenge A new synthetic process for such a reaction

is presented in Chapter 2

12 Synthesis of allylboronates

Allylboronates are efficient reagents for regio- and stereoselective allyla-

tion of carbonyl compounds and some related functionalities3 12

Due to the

importance of allylboronates in synthetic organic chemistry there has been a

large interest in the development of new methods for the synthesis of these

reagents The classical synthetic procedures involve application of allyl-

Grignard and allyl-Li reagents13

However these methods have a limited

synthetic scope because of problems with the regioselective formation of the

allylboronates Palladium-catalyzed methods based on the substitution of allylic alcohol

derivatives have proven to be a versatile and relatively simple method to

obtain allylboronates The first process was reported by Miyaura and

co-workers14

(Scheme 3) In this process B2pin2 was used as the boron

source Although the regioselectivity of the reaction is excellent a drawback

of this process is the formation of varying amounts of homocoupling prod-

ucts

Scheme 3 Pd-catalyzed borylation of allylacetates

14

The Szaboacute group15

has expanded the substrate scope to include allylic

alcohols instead of allylic acetates (Scheme 4) It was also shown that

3

certain Pd(II) pincer complexes are more efficient than Pd(dba)2 In depth

mechanistic studies revealed that catalytic amounts of Lewis or Broslashnsted

acids are required in the reaction to activate the allylic alcohols for Pd-

catalyzed substitution16

The reaction is substantially accelerated in the pres-

ence of MeOH or other protic co-solvents

Scheme 4 Pd-catalyzed borylation of allylic alcohols

15c 15d

The Szaboacute group also developed palladium-catalyzed allylic C-H boryla-

tion methods17

These processes allowed for the synthesis of allylboronates

from readily available alkenes under oxidative conditions using BQ (1) or

the hypervalent iodonium salt

Ito Sawamura and their co-workers reported the regio- and stereoselec-

tive synthesis of allylboronates by Cu-catalyzed substitution of allyl

carbonates18

This method can also be extended to asymmetric catalysis for

the synthesis of enantioenriched allylboronates (Scheme 5)19

Scheme 5 Cu-catalyzed asymmetric borylation of allylcarbonates

19

Enantioselective synthesis of α-substituted allylboronates has been

reported by Hall and co-workers (Scheme 6)20

This method is based on

copper-catalyzed substitution of allylhalide substrates The chiral

allylboronates generated in this reaction were used for further transformation

without isolation

Scheme 6 Cu-catalyzed borylation reported by Hall and co-workers

20

Related Cu-catalyzed asymmetric synthesis of allylboronates have also

been independently reported by the groups of Hoveyda21

and McQuade22

Nickel-catalyzed stereospecific borylation of allylic acetates was developed

by Morken and co-workers23

The reaction is highly selective for the termi-

4

nal allylboronates (Scheme 7) The Morken group also developed palladi-

um-catalyzed enantioselective borylation methods for the synthesis of al-

lylboronates24

Scheme 7 Ni-catalyzed selective borylation of allylic acetates

23

Very recently Aggarwal and co-workers have reported a new method for

the preparation of enantioenriched allylboronates25

This so called ldquolithia-

tion-borylation methodrdquo involves homologation of vinyl boronates using

alkyl carbamates and butyllithium (BuLi) in the presence of (+)-sparteine

(Scheme 8)

Scheme 8 Synthesis of allylboronates by lithiation-borylation method

25b

As shown above synthesis of allylboron reagents has attracted large in-

terest in modern organic chemistry As a contribution to this field we devel-

oped a new method for the synthesis and isolation of allylboronic acids

which is presented in Chapter 3

13 Application of allylboronates in synthesis

Allylboronate reagents have been extensively used to synthesize numerous precursors for natural products and bioactive molecules

26

Addition of allylboronates to carbonyl and imine electrophiles is a well studied and documented reactions in synthetic organic chemistry

131 Stereoselective allylation of carbonyl compounds

Allylboration reactions of aldehydes have been widely applied for the ste-

reoselective synthesis of homoallylic alcohols3 After the discovery by Bub-

nov27

the reaction was further developed by Hoffmann28

Brown29

Roush30

and others Hoffmann and Brown carried out in depth mechanistic studies

which also explained the stereochemistry of the reaction Hoffman postulat-

ed that the reaction between allylboronates and aldehydes proceeds via a six-

5

membered cyclic TS similar to the Zimmerman-Traxler31

model (Scheme

9)28a 32

The high diastereoselectivity of the allylboration reaction is attributed to

an internal Lewis acid activation of the carbonyl functionality by the empty

p-orbital of boron

Scheme 9 Zimmerman-Traxler model to describe stereochemistry of allylboration

reaction

The addition of Lewis or Broslashnsted acids may accelerate the allylboration

of carbonyl compounds33

Hall and co-workers proposed that Lewis acids

coordinate to the lone pair of the boronate oxygen which renders the boron

atom more electron deficient (Scheme 10)33b 34

This mechanism for LA

and Broslashnsted acid activation was also confirmed by the DFT studies of

Houk and co-workers35

Scheme 10 Possible modes of Lewis acid activation for the allylboration

Allylboronates can also react with ketones yielding tertiary homoallylic

alcohols However the addition of allylboronates to ketones is much slower

than similar reactions with aldehydes Thus the selective allylation of

ketones with allylboronates often requires the use of catalysts36

In addition

most of the present methods for allylboration of ketones are limited to the

use of unsubstituted (parent) allylboronates or crotylboronates

132 Enantioselective allylation of carbonyl compounds

There are basically two main approaches for the asymmetric allylboration

of carbonyl compounds The first approach is the application of enantioen-

riched allylboronates performing chirality transfer and the second one is

6

asymmetric induction by using chiral catalyst One of the first asymmetric

allylboration reactions was reported by Roush and co-workers 13b 37

These

authors employed chiral auxiliaries attached to the boron atom (Scheme 11)

Diisopropyl tartrate (DIPT) proved to be a very efficient chiral auxiliary to

induce enantioselectivity

Scheme 11 Asymmetric allylation of aldehydes using chiral allylboronate

13b

A similar approach was reported by Soderquist and co-workers38

for the

asymmetric allylboration of aldehyde and ketones A bicyclic chiral auxilia-

ry on the boron atom was employed for highly diastereo- and enantioselec-

tive allylboration (Scheme 12)

Scheme 12 Diastereo-and enantioselective allylboration by chiral allylborane

38a

Enantiomerically pure TADDOL based allylboronates were developed by

Pietruszka and co-workers39

These reagents were used for chirality transfer

in allylboration of aldehydes (Scheme 13) The chiral auxiliary can be

recovered after the allylation by reduction with LiAlH4

Scheme 13 Asymmetric allylation of aldehyde using enantiopure allylboronate

39

Metal-catalyzed asymmetric synthesis of heterocyclic allylboronates was

described by Hall and co-workers40

These allylboronates were used in situ

for allylboration of aldehydes The key-step in synthesis of mefloquine was

performed using this method (Scheme 14)

7

Scheme 14 Asymmetric allylboration by cyclic allylboronates

40

Very recently Aggarwal and co-workers25b 41

reported an efficient

allylboration method using α-substituted enantioenriched allylboronates (see

also Scheme 8) The method is highly diastereo- and enantioselective In

addition the procedure is suitable for the synthesis of homoallylic alcohols

with two adjacent quaternary stereocenters (Scheme 15)

Scheme 15 Asymmetric allylation of ketone by α-substituted chiral allylboronate

25b

An alternative approach for the asymmetric allylboration of carbonyl

compounds involves the application of chiral catalysts Both Lewis and

Broslashnsted acids have been used for the asymmetric allylboration reactions

The first catalytic enantioselective allylboration reaction was reported by

Miyaura and co-workers (Scheme 16)33c

This reaction proceeded with a

high regio- and diastereoselectivity but the enantioselectivity was relatively

low

Scheme 16 Catalytic asymmetric allylboration of aldehyde

33c

Hall and co-workers42

reported a Sn-catalyzed asymmetric allylboration

reaction using allyl-Bpin as the allyl source A chiral diol was used as a lig-

and in this process which was supposed to coordinate to SnCl4 (Scheme 17)

8

Scheme 17 Tin-catalyzed asymmetric allylboration of aldehyde

42a

Asymmetric allylation of ketones was reported using chiral allylboronate

derived from BINOL compounds Chong and co-workers described the al-

lylation of ketones using 33-(CF3)2-BINOL boronate 3a (Scheme 18)43

The

reaction gave homoallylic alcohol product with a high level of enantioselec-

tivity

Scheme 18 Asymmetric allylation of ketone using BINOL-boronate

43

Catalytic methods have also been described to control both diastereo- and

enantioselectivity in the allylboration of ketones44

The first catalytic

enantioselective allylboration of ketones was developed by Shibasaki and

co-workers45

Broslashnsted acid such as BINOL derivatives44 46

was found to be

very efficient in the asymmetric allylboration reactions Schaus and

co-workers44

reported a method for asymmetric allylation of ketones using

isopropoxyboronate and catalytic amounts of Br2-BINOL 4a (Scheme 19)

Scheme 19 Catalytic asymmetric allylboration of ketone using Br2-BINOL

44a

These authors proposed a Zimmerman-Traxler type transition state to

rationalize the enantioselectivity in this reaction It has been also pointed out

that the substituent in BINOL (eg Br or CF3) has an important role for the

enantioselectivity of these reactions

Catalytic synthesis of homoallylic alcohols containing adjacent quater-

nary stereocenters has been a great challenge in synthetic organic chemistry

A new synthetic method for such reaction is presented in Section 52

9

133 Stereoselective allylation of imines

Homoallylic amine motifs occur in many natural products and biological-

ly relevant compounds47

One of the most common strategies for homoallylic

amine synthesis is the addition of allyl-metal reagents to imines48

The use of

allylboronate compounds for these reactions has emerged as an important

synthetic approach47

Allylboronates have a low toxicity high functional

group tolerance and the allylation of imines occurs with a high level of

selectivity

Stereoselective allylation of aldimines can be performed by

allylboronates in the presence of Lewis acid catalysts Batey and

co-workers49

reported the allylboration of N-toluenesulfonylimines using

crotyltrifluroboronate and BF3OEt2 (Scheme 20) The allylation was

proposed to proceed via the allyl-BF2 species which is generated from

allyl-BF3K

Scheme 20 Stereoselective allylation of imine by allyltrifluoroborate

49

Kobayashi and co-workers50

reported a three-component diastereoselec-

tive allylation reaction to synthesize homoallylic primary amines (Scheme

21) In addition several useful methods for asymmetric allylboration of

imines25b 51

using allylboronates can also be found in literature

Scheme 21 Synthesis of homoallylic amine using multicomponent method

50

Allylboration of acylhydrazones have also proven to be a very useful

reaction for the synthesis of homoallylic amine derivatives However the

allylation of acylhydrazones by allylboronates requires the application of

metal catalysts52

An indium-catalyzed reaction for the allylation of N-

acylhydrazone was reported by Kobayashi and co-workers (Scheme 22)52a

It

has been proposed that indium undergoes a transmetallation with allyl-Bpin

to form an active allyl-indium species which then added to the hydrazone

10

Scheme 22 Indium-catalyzed allylation of acylhydrazone

52a

We have developed a stereoselective method for allylation of imines and

acylhydrazones using allylboronic acids These results are summarized in

Chapter 6

11

2 Pd-catalyzed stereoselective allylic CminusH

trifluoroacetoxylation (Paper I)

As mentioned in the introduction transition metal-catalyzed CminusH bond activation methods have attracted increasing interest in organic synthesis

53

Using these methods multistep synthesis for prefunctionalization of the or-ganic substrates is not necessary In addition the waste production of the reaction can be reduced as the new functional group can be installed by re-placement of hydrogen

54 Palladium-catalyzed allylic CminusH bond activation is

one of the oldest and most versatile CminusH functionalization method (Section 11)

55 In this reaction (as in CminusH activation based processes in general) the

greatest challenge is the control of the regio- and stereoselectivity of the process

Stereodefined allylic acetates are very important precursors for regio- and stereoselective palladium-catalyzed allylic substitution reactions

56 Although

many regioselective allylic CminusH functionalization methods have been re-ported there are few reports on stereoselective allylic CminusH acetoxylation

7a

Most of these studies are intramolecular CminusH acyloxylation reactions For example a stereoselective allylic CminusH acetoxylation method has been re-ported by White and co-workers (Scheme 23) Intramolecular selectivity control allowed macrocyclization

57 and straightforward synthesis of anti-14-

dioxan-2-ones58

from simple olefins using Pd(II)sulfoxide catalysis Baumlck-vall and co-workers

59 have also developed several methods for the synthesis

of allylacetoxy compounds based on palladium-catalyzed intramolecular oxidative carbocyclization

Scheme 23 Stereoselective intramolecular CminusH oxidation reported by White and

co-workers58

12

21 Development of selective intermolecular allylic CminusH trifluoroacetoxylation

As our group previously developed a useful allylic CminusH acetoxylation

method based on using PhI(OAc)2 (2a) (see Section 11) as oxidant and ace-

tate source we envisioned that PhI(OCOCF3)2 (2b) can also be used in this

type of reaction to introduce a trifluoroacetate group at the allylic position of

alkenes Allylic trifluoroacetates are more reactive than allylic acetates in

transition metal-catalyzed substitutions60

and therefore an easy access to

these compounds is desirable As far as we know selective allylic CminusH tri-

fluoroacetoxylation has not been reported in the literature

In the early stage of development and optimization we employed car-

boxylated alkene 6a as our model substrate as it gave a high yield and ex-

hibited high selectivity in the Pd-catalyzed CminusH acetoxylation with 2a11b

However PhI(OCOCF3)2 (2b) is most likely a stronger oxidant than

PhI(OAc)2 (2a) and therefore we could not use oxidation sensitive solvents

such as THF or DMSO In addition the conjugated acid of the trifluoroace-

tate ion (the nucleophile) is a strong acid and therefore trifluoroacetic acid

could not be used as the solvent either After short optimization we have

found that dimethyl carbonate (DMC) is an excellent solvent for all reaction

components and it is not oxidized by PIFA We have found that the isolated

yields are higher when LiOCOCF3 is used as additive Under these condi-

tions the reaction could be performed with various functionalized alkenes

(Table 1)

13

Table 1 Pd-catalyzed allylic CminusH trifluoroacetoxylation of acyclic olefinsa

Both Pd(OAc)2 (5b) and Pd(OCOCF3)2 (5c) were equally efficient as cat-

alyst in the reaction So we decided to use 5b in the present synthetic method

as it is less expensive than 5c Not only terminal (6a) but internal alkenes

6b-c could also be used for trifluoroacetoxylation with high selectivity Oth-

er alkenes with electron withdrawing substituents such as 6d-e could also be

smoothly trifluoroacetoxylated Substrates without electron-withdrawing

groups gave intractable mixtures of trifluoroacetoxylated products For com-

pounds with long alkyl chain oxidation of the double bond occurred while in

the case of electron donating substituents mainly oxidation of the double

bond occurred together with other processes

14

Table 2 Stereoselective allylic CminusH trifluoroacetoxylation of cyclic alkenesa

Not only acyclic alkenes but cyclic alkenes could also be employed for

the trifluoroacetoxylation reaction Monosubstituted cyclic alkenes reacted

with a remarkably high selectivity (Table 2) The reaction conditions were

very similar to the trifluoroacetoxylation of acyclic substrates (Table 1) but

in order to get this high stereoselectivity the reactions had to be conducted

at 0 degC This is below the freezing point of DMC therefore the reaction me-

dium was diluted with DCM to avoid freezing of the reaction mixture The

yields with LiOCOCF3 were as high as in its absence therefore we did not

use this additive in the trifluoroacetoxylation of cyclic substrates

Considering the number of possible regio- and stereoisomers a mixture

of six allylic trifluoroacetate products could be expected Yet in most cases

we obtained a single diastereomer with very high regioselectivity (Table 2

entries 1-2 and 4-5) The major regioisomer in all cases was the 14-

substituted product (7f-j) with anti diastereoselectivity and the minor prod-

uct is the regioisomer of the same diastereomer The stereochemistry of the

major isomers was assigned based on NOE experiments

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

1 The ACS Style Guide 3rd ed Oxford University Press New York 2006

2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

vii

List of Publications

This thesis is based on a licentiate thesis by Rauful Alam entitled ldquoPalladi-

um-catalyzed Allylic CminusH and CminusOH Functionalization Reactions of the

Obtained Allylboronic Acidsrdquo and the following papers referred to in text

by their Roman numerals I-VI Reprints were made with the kind permission

from the publishers (Appendix A)

I Stereoselective Intermolecular Allylic C-H Trifluoroacetoxylation

of Functionalized Alkenes

Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

II Palladium-Catalyzed Synthesis and Isolation of Functionalized

Allylboronic Acids Facile Direct Allylboration of Ketones Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

III Selective Formation of Adjacent Stereocenters by Allylboration of

Ketones under Mild Neutral Conditions Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

IV Synthesis of Adjacent Quaternary Stereocenters by Catalytic

Asymmetric Allylboration

Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

V Stereoselective Allylboration of Imines and Indoles under Mild

Conditions An in situ EZ Isomerization of Imines by Allylborox-

ines Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

VI Stereocontrol in Synthesis of Homoallylic Amines Syn Selective

Direct Allylation of Hydrazones with Allylboronic Acids Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

viii

Contents

Abstract v

List of Publications vii

Contents viii

Abbreviations xi

1 Introduction 1

11 Palladium-catalyzed allylic CminusH acetoxylation 1

12 Synthesis of allylboronates 2

13 Application of allylboronates in synthesis 4

131 Stereoselective allylation of carbonyl compounds 4

132 Enantioselective allylation of carbonyl compounds 5

133 Stereoselective allylation of imines 9

2 Pd-catalyzed stereoselective allylic CminusH trifluoroacetoxylation (Paper I) 11

21 Development of selective intermolecular allylic CminusH

trifluoroacetoxylationhelliphelliphelliphellip 12

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation 15

23 Conclusions for the allylic CminusH trifluoroacetoxylation 17

3 Pd-catalyzed synthesis and isolation of allylboronic acids (Paper II) 18

31 Development of new synthetic methods for the synthesis and isolation of

allylboronic acids 18

311 Diboronic acid B2(OH)4 as boron source 19

312 Synthesis of allylboronic acids and their isolation 20

32 Characterization of allylboroxine 22

33 Proposed mechanism for the allylic CminusOH borylation 24

34 Conclusions for the allylic CminusOH borylation 25

4 Allylboration of carbonyl compounds using allylboronic acids (Paper II-III) 26

41 Allylation of ketones by allylboronic acids 26

42 Stereoselectivity of α-hydroxy acids 31

43 Conclusions for allylboration of carbonyl compounds 32

ix

5 Synthesis of adjacent quaternary stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV) 33

51 Method development for the asymmetric allylboration of ketones helliphellip33

52 Stereocontrol in the asymmetric allylboration of ketone 35

53 Catalytic enantioselective allylboration of ketones 36

54 Proposed mechanism for the enantioselectivity of the allylboration of

ketones with allylboronic acids 38

541 Proposed models for enantioselectivity 40

542 Proposed catalytic cycle 41

55 Conclusions for the catalytic asymmetric allylboration 42

6 Allylboration of imines indoles and hydrazones (Paper V-VI) 43

61 Allylation of imines with allylboronic acids 43

62 Allylation of indoles with allylboronic acids 46

63 Allylation of acyl hydrazones with allylboronic acids 48

64 Mechanistic study and proposal for the allylation of aldimines 50

65 Proposed mechanism for the allylboration of hydrazones 52

66 Proposed mechanism for the allylboration of indoles 54

67 Conclusions for the allylboration of imines indoles and hydrazones 55

7 Concluding remarks 56

8 Acknowledgements 57

9 Summary in Swedish 58

10 Appendix A 59

11 References 60

x

xi

Abbreviations

Abbreviations are used in agreement with standards of the subject1 Addi-

tional non-standard or unconventional abbreviations that appear in this thesis

are listed below

B2pin2 bis(pinacolato)diboron

BINOL 11-bi-2-naphthol

Bpin pinacolato boron

BQ 14-benzoquinone

dba dibenzylideneacetone

DFT density functional theory

DMC dimethyl carbonate

dr diastereomeric ratio

er enantiomeric ratio

LA Lewis acid

L ligand (neutral)

L chiral ligand

MS molecular sieves

NOE nuclear Overhauser effect

PIFA phenyliodine bis(trifluoroacetate)

PIDA phenyliodonium diacetate

TFA trifluoroacetate

TS transition state

rt room temperature

X ligand (charged)

1

1 Introduction

The development of highly selective transformations is of fundamental

importance in modern organic chemistry Transition metal-catalysis is one of

the useful synthetic approaches to achieve this goal2 The allylation reaction

using allylboron reagents and other allyl sources is also an important ap-

proach to develop selective syntheses3

11 Palladium-catalyzed allylic CminusH acetoxylation

Transition metal-catalyzed substitution of allylic acetates and their ana-

logs is one of the most utilized and studied reactions4 An important method

to synthesize allylic acetates is Pd-catalyzed allylic CminusH functionalization5

Pioneering works by McMurry and Kocovsky6 and Aringkermark

7 have shown

that Pd(II)-catalyzed allylic acetoxylation of cyclic and acyclic olefins can

be achieved in the presence of acetic acid and benzoquinone (BQ) as oxidant

(Scheme 1) Mechanistic investigations by Baumlckvall8 and co-workers

indicated that a (π-allyl)palladium(II) intermediates are involved in the

process and that BQ serves as both oxidant and activator ligand in the

CminusOAc bond formation process

Scheme 1 Pd-catalyzed allylic CminusH acetoxylation reaction

7a

Recently the White9 and the Stahl

10 group independently reported new

methods for CminusH acetoxylation reactions using palladium catalysis The

latter group used O2 as an oxidant instead of BQ According to the mechanis-

tic studies by these authors the CminusH acetoxylation process take place via

Pd0 and Pd

II catalytic intermediates

Hypervalent iodine reagents were also employed as the principal compo-

nent in the allylic CminusH oxidation reactions5 11

For example Szaboacute and

co-workers11b

have reported the allylic CminusH acyloxylation reaction with

PhI(OAc)2 (2a) as the oxidant and source of OAc (Scheme 2) The use of a

2

palladium catalysts and hypervalent iodine reagents allowed an easy access

to allylic acetoxy and benzoyloxy compounds Based on the mechanistic

studies a PdIIPd

IV catalytic cycle was proposed when PhI(OAc)2 was used

as the oxidant

Scheme 2 Pd-catalyzed CminusH acetoxylation reaction reported by Szaboacute and co-

workers11b

In spite of the wide application of allylic CminusH acyloxylation reactions in

organic synthesis the stereoselective transformations of substituted cyclic

alkenes are limited Particularly the intermolecular diastereoselective CminusH

acyloxylation is still a challenge A new synthetic process for such a reaction

is presented in Chapter 2

12 Synthesis of allylboronates

Allylboronates are efficient reagents for regio- and stereoselective allyla-

tion of carbonyl compounds and some related functionalities3 12

Due to the

importance of allylboronates in synthetic organic chemistry there has been a

large interest in the development of new methods for the synthesis of these

reagents The classical synthetic procedures involve application of allyl-

Grignard and allyl-Li reagents13

However these methods have a limited

synthetic scope because of problems with the regioselective formation of the

allylboronates Palladium-catalyzed methods based on the substitution of allylic alcohol

derivatives have proven to be a versatile and relatively simple method to

obtain allylboronates The first process was reported by Miyaura and

co-workers14

(Scheme 3) In this process B2pin2 was used as the boron

source Although the regioselectivity of the reaction is excellent a drawback

of this process is the formation of varying amounts of homocoupling prod-

ucts

Scheme 3 Pd-catalyzed borylation of allylacetates

14

The Szaboacute group15

has expanded the substrate scope to include allylic

alcohols instead of allylic acetates (Scheme 4) It was also shown that

3

certain Pd(II) pincer complexes are more efficient than Pd(dba)2 In depth

mechanistic studies revealed that catalytic amounts of Lewis or Broslashnsted

acids are required in the reaction to activate the allylic alcohols for Pd-

catalyzed substitution16

The reaction is substantially accelerated in the pres-

ence of MeOH or other protic co-solvents

Scheme 4 Pd-catalyzed borylation of allylic alcohols

15c 15d

The Szaboacute group also developed palladium-catalyzed allylic C-H boryla-

tion methods17

These processes allowed for the synthesis of allylboronates

from readily available alkenes under oxidative conditions using BQ (1) or

the hypervalent iodonium salt

Ito Sawamura and their co-workers reported the regio- and stereoselec-

tive synthesis of allylboronates by Cu-catalyzed substitution of allyl

carbonates18

This method can also be extended to asymmetric catalysis for

the synthesis of enantioenriched allylboronates (Scheme 5)19

Scheme 5 Cu-catalyzed asymmetric borylation of allylcarbonates

19

Enantioselective synthesis of α-substituted allylboronates has been

reported by Hall and co-workers (Scheme 6)20

This method is based on

copper-catalyzed substitution of allylhalide substrates The chiral

allylboronates generated in this reaction were used for further transformation

without isolation

Scheme 6 Cu-catalyzed borylation reported by Hall and co-workers

20

Related Cu-catalyzed asymmetric synthesis of allylboronates have also

been independently reported by the groups of Hoveyda21

and McQuade22

Nickel-catalyzed stereospecific borylation of allylic acetates was developed

by Morken and co-workers23

The reaction is highly selective for the termi-

4

nal allylboronates (Scheme 7) The Morken group also developed palladi-

um-catalyzed enantioselective borylation methods for the synthesis of al-

lylboronates24

Scheme 7 Ni-catalyzed selective borylation of allylic acetates

23

Very recently Aggarwal and co-workers have reported a new method for

the preparation of enantioenriched allylboronates25

This so called ldquolithia-

tion-borylation methodrdquo involves homologation of vinyl boronates using

alkyl carbamates and butyllithium (BuLi) in the presence of (+)-sparteine

(Scheme 8)

Scheme 8 Synthesis of allylboronates by lithiation-borylation method

25b

As shown above synthesis of allylboron reagents has attracted large in-

terest in modern organic chemistry As a contribution to this field we devel-

oped a new method for the synthesis and isolation of allylboronic acids

which is presented in Chapter 3

13 Application of allylboronates in synthesis

Allylboronate reagents have been extensively used to synthesize numerous precursors for natural products and bioactive molecules

26

Addition of allylboronates to carbonyl and imine electrophiles is a well studied and documented reactions in synthetic organic chemistry

131 Stereoselective allylation of carbonyl compounds

Allylboration reactions of aldehydes have been widely applied for the ste-

reoselective synthesis of homoallylic alcohols3 After the discovery by Bub-

nov27

the reaction was further developed by Hoffmann28

Brown29

Roush30

and others Hoffmann and Brown carried out in depth mechanistic studies

which also explained the stereochemistry of the reaction Hoffman postulat-

ed that the reaction between allylboronates and aldehydes proceeds via a six-

5

membered cyclic TS similar to the Zimmerman-Traxler31

model (Scheme

9)28a 32

The high diastereoselectivity of the allylboration reaction is attributed to

an internal Lewis acid activation of the carbonyl functionality by the empty

p-orbital of boron

Scheme 9 Zimmerman-Traxler model to describe stereochemistry of allylboration

reaction

The addition of Lewis or Broslashnsted acids may accelerate the allylboration

of carbonyl compounds33

Hall and co-workers proposed that Lewis acids

coordinate to the lone pair of the boronate oxygen which renders the boron

atom more electron deficient (Scheme 10)33b 34

This mechanism for LA

and Broslashnsted acid activation was also confirmed by the DFT studies of

Houk and co-workers35

Scheme 10 Possible modes of Lewis acid activation for the allylboration

Allylboronates can also react with ketones yielding tertiary homoallylic

alcohols However the addition of allylboronates to ketones is much slower

than similar reactions with aldehydes Thus the selective allylation of

ketones with allylboronates often requires the use of catalysts36

In addition

most of the present methods for allylboration of ketones are limited to the

use of unsubstituted (parent) allylboronates or crotylboronates

132 Enantioselective allylation of carbonyl compounds

There are basically two main approaches for the asymmetric allylboration

of carbonyl compounds The first approach is the application of enantioen-

riched allylboronates performing chirality transfer and the second one is

6

asymmetric induction by using chiral catalyst One of the first asymmetric

allylboration reactions was reported by Roush and co-workers 13b 37

These

authors employed chiral auxiliaries attached to the boron atom (Scheme 11)

Diisopropyl tartrate (DIPT) proved to be a very efficient chiral auxiliary to

induce enantioselectivity

Scheme 11 Asymmetric allylation of aldehydes using chiral allylboronate

13b

A similar approach was reported by Soderquist and co-workers38

for the

asymmetric allylboration of aldehyde and ketones A bicyclic chiral auxilia-

ry on the boron atom was employed for highly diastereo- and enantioselec-

tive allylboration (Scheme 12)

Scheme 12 Diastereo-and enantioselective allylboration by chiral allylborane

38a

Enantiomerically pure TADDOL based allylboronates were developed by

Pietruszka and co-workers39

These reagents were used for chirality transfer

in allylboration of aldehydes (Scheme 13) The chiral auxiliary can be

recovered after the allylation by reduction with LiAlH4

Scheme 13 Asymmetric allylation of aldehyde using enantiopure allylboronate

39

Metal-catalyzed asymmetric synthesis of heterocyclic allylboronates was

described by Hall and co-workers40

These allylboronates were used in situ

for allylboration of aldehydes The key-step in synthesis of mefloquine was

performed using this method (Scheme 14)

7

Scheme 14 Asymmetric allylboration by cyclic allylboronates

40

Very recently Aggarwal and co-workers25b 41

reported an efficient

allylboration method using α-substituted enantioenriched allylboronates (see

also Scheme 8) The method is highly diastereo- and enantioselective In

addition the procedure is suitable for the synthesis of homoallylic alcohols

with two adjacent quaternary stereocenters (Scheme 15)

Scheme 15 Asymmetric allylation of ketone by α-substituted chiral allylboronate

25b

An alternative approach for the asymmetric allylboration of carbonyl

compounds involves the application of chiral catalysts Both Lewis and

Broslashnsted acids have been used for the asymmetric allylboration reactions

The first catalytic enantioselective allylboration reaction was reported by

Miyaura and co-workers (Scheme 16)33c

This reaction proceeded with a

high regio- and diastereoselectivity but the enantioselectivity was relatively

low

Scheme 16 Catalytic asymmetric allylboration of aldehyde

33c

Hall and co-workers42

reported a Sn-catalyzed asymmetric allylboration

reaction using allyl-Bpin as the allyl source A chiral diol was used as a lig-

and in this process which was supposed to coordinate to SnCl4 (Scheme 17)

8

Scheme 17 Tin-catalyzed asymmetric allylboration of aldehyde

42a

Asymmetric allylation of ketones was reported using chiral allylboronate

derived from BINOL compounds Chong and co-workers described the al-

lylation of ketones using 33-(CF3)2-BINOL boronate 3a (Scheme 18)43

The

reaction gave homoallylic alcohol product with a high level of enantioselec-

tivity

Scheme 18 Asymmetric allylation of ketone using BINOL-boronate

43

Catalytic methods have also been described to control both diastereo- and

enantioselectivity in the allylboration of ketones44

The first catalytic

enantioselective allylboration of ketones was developed by Shibasaki and

co-workers45

Broslashnsted acid such as BINOL derivatives44 46

was found to be

very efficient in the asymmetric allylboration reactions Schaus and

co-workers44

reported a method for asymmetric allylation of ketones using

isopropoxyboronate and catalytic amounts of Br2-BINOL 4a (Scheme 19)

Scheme 19 Catalytic asymmetric allylboration of ketone using Br2-BINOL

44a

These authors proposed a Zimmerman-Traxler type transition state to

rationalize the enantioselectivity in this reaction It has been also pointed out

that the substituent in BINOL (eg Br or CF3) has an important role for the

enantioselectivity of these reactions

Catalytic synthesis of homoallylic alcohols containing adjacent quater-

nary stereocenters has been a great challenge in synthetic organic chemistry

A new synthetic method for such reaction is presented in Section 52

9

133 Stereoselective allylation of imines

Homoallylic amine motifs occur in many natural products and biological-

ly relevant compounds47

One of the most common strategies for homoallylic

amine synthesis is the addition of allyl-metal reagents to imines48

The use of

allylboronate compounds for these reactions has emerged as an important

synthetic approach47

Allylboronates have a low toxicity high functional

group tolerance and the allylation of imines occurs with a high level of

selectivity

Stereoselective allylation of aldimines can be performed by

allylboronates in the presence of Lewis acid catalysts Batey and

co-workers49

reported the allylboration of N-toluenesulfonylimines using

crotyltrifluroboronate and BF3OEt2 (Scheme 20) The allylation was

proposed to proceed via the allyl-BF2 species which is generated from

allyl-BF3K

Scheme 20 Stereoselective allylation of imine by allyltrifluoroborate

49

Kobayashi and co-workers50

reported a three-component diastereoselec-

tive allylation reaction to synthesize homoallylic primary amines (Scheme

21) In addition several useful methods for asymmetric allylboration of

imines25b 51

using allylboronates can also be found in literature

Scheme 21 Synthesis of homoallylic amine using multicomponent method

50

Allylboration of acylhydrazones have also proven to be a very useful

reaction for the synthesis of homoallylic amine derivatives However the

allylation of acylhydrazones by allylboronates requires the application of

metal catalysts52

An indium-catalyzed reaction for the allylation of N-

acylhydrazone was reported by Kobayashi and co-workers (Scheme 22)52a

It

has been proposed that indium undergoes a transmetallation with allyl-Bpin

to form an active allyl-indium species which then added to the hydrazone

10

Scheme 22 Indium-catalyzed allylation of acylhydrazone

52a

We have developed a stereoselective method for allylation of imines and

acylhydrazones using allylboronic acids These results are summarized in

Chapter 6

11

2 Pd-catalyzed stereoselective allylic CminusH

trifluoroacetoxylation (Paper I)

As mentioned in the introduction transition metal-catalyzed CminusH bond activation methods have attracted increasing interest in organic synthesis

53

Using these methods multistep synthesis for prefunctionalization of the or-ganic substrates is not necessary In addition the waste production of the reaction can be reduced as the new functional group can be installed by re-placement of hydrogen

54 Palladium-catalyzed allylic CminusH bond activation is

one of the oldest and most versatile CminusH functionalization method (Section 11)

55 In this reaction (as in CminusH activation based processes in general) the

greatest challenge is the control of the regio- and stereoselectivity of the process

Stereodefined allylic acetates are very important precursors for regio- and stereoselective palladium-catalyzed allylic substitution reactions

56 Although

many regioselective allylic CminusH functionalization methods have been re-ported there are few reports on stereoselective allylic CminusH acetoxylation

7a

Most of these studies are intramolecular CminusH acyloxylation reactions For example a stereoselective allylic CminusH acetoxylation method has been re-ported by White and co-workers (Scheme 23) Intramolecular selectivity control allowed macrocyclization

57 and straightforward synthesis of anti-14-

dioxan-2-ones58

from simple olefins using Pd(II)sulfoxide catalysis Baumlck-vall and co-workers

59 have also developed several methods for the synthesis

of allylacetoxy compounds based on palladium-catalyzed intramolecular oxidative carbocyclization

Scheme 23 Stereoselective intramolecular CminusH oxidation reported by White and

co-workers58

12

21 Development of selective intermolecular allylic CminusH trifluoroacetoxylation

As our group previously developed a useful allylic CminusH acetoxylation

method based on using PhI(OAc)2 (2a) (see Section 11) as oxidant and ace-

tate source we envisioned that PhI(OCOCF3)2 (2b) can also be used in this

type of reaction to introduce a trifluoroacetate group at the allylic position of

alkenes Allylic trifluoroacetates are more reactive than allylic acetates in

transition metal-catalyzed substitutions60

and therefore an easy access to

these compounds is desirable As far as we know selective allylic CminusH tri-

fluoroacetoxylation has not been reported in the literature

In the early stage of development and optimization we employed car-

boxylated alkene 6a as our model substrate as it gave a high yield and ex-

hibited high selectivity in the Pd-catalyzed CminusH acetoxylation with 2a11b

However PhI(OCOCF3)2 (2b) is most likely a stronger oxidant than

PhI(OAc)2 (2a) and therefore we could not use oxidation sensitive solvents

such as THF or DMSO In addition the conjugated acid of the trifluoroace-

tate ion (the nucleophile) is a strong acid and therefore trifluoroacetic acid

could not be used as the solvent either After short optimization we have

found that dimethyl carbonate (DMC) is an excellent solvent for all reaction

components and it is not oxidized by PIFA We have found that the isolated

yields are higher when LiOCOCF3 is used as additive Under these condi-

tions the reaction could be performed with various functionalized alkenes

(Table 1)

13

Table 1 Pd-catalyzed allylic CminusH trifluoroacetoxylation of acyclic olefinsa

Both Pd(OAc)2 (5b) and Pd(OCOCF3)2 (5c) were equally efficient as cat-

alyst in the reaction So we decided to use 5b in the present synthetic method

as it is less expensive than 5c Not only terminal (6a) but internal alkenes

6b-c could also be used for trifluoroacetoxylation with high selectivity Oth-

er alkenes with electron withdrawing substituents such as 6d-e could also be

smoothly trifluoroacetoxylated Substrates without electron-withdrawing

groups gave intractable mixtures of trifluoroacetoxylated products For com-

pounds with long alkyl chain oxidation of the double bond occurred while in

the case of electron donating substituents mainly oxidation of the double

bond occurred together with other processes

14

Table 2 Stereoselective allylic CminusH trifluoroacetoxylation of cyclic alkenesa

Not only acyclic alkenes but cyclic alkenes could also be employed for

the trifluoroacetoxylation reaction Monosubstituted cyclic alkenes reacted

with a remarkably high selectivity (Table 2) The reaction conditions were

very similar to the trifluoroacetoxylation of acyclic substrates (Table 1) but

in order to get this high stereoselectivity the reactions had to be conducted

at 0 degC This is below the freezing point of DMC therefore the reaction me-

dium was diluted with DCM to avoid freezing of the reaction mixture The

yields with LiOCOCF3 were as high as in its absence therefore we did not

use this additive in the trifluoroacetoxylation of cyclic substrates

Considering the number of possible regio- and stereoisomers a mixture

of six allylic trifluoroacetate products could be expected Yet in most cases

we obtained a single diastereomer with very high regioselectivity (Table 2

entries 1-2 and 4-5) The major regioisomer in all cases was the 14-

substituted product (7f-j) with anti diastereoselectivity and the minor prod-

uct is the regioisomer of the same diastereomer The stereochemistry of the

major isomers was assigned based on NOE experiments

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

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16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

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20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

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1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

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34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

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45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

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64

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viii

Contents

Abstract v

List of Publications vii

Contents viii

Abbreviations xi

1 Introduction 1

11 Palladium-catalyzed allylic CminusH acetoxylation 1

12 Synthesis of allylboronates 2

13 Application of allylboronates in synthesis 4

131 Stereoselective allylation of carbonyl compounds 4

132 Enantioselective allylation of carbonyl compounds 5

133 Stereoselective allylation of imines 9

2 Pd-catalyzed stereoselective allylic CminusH trifluoroacetoxylation (Paper I) 11

21 Development of selective intermolecular allylic CminusH

trifluoroacetoxylationhelliphelliphelliphellip 12

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation 15

23 Conclusions for the allylic CminusH trifluoroacetoxylation 17

3 Pd-catalyzed synthesis and isolation of allylboronic acids (Paper II) 18

31 Development of new synthetic methods for the synthesis and isolation of

allylboronic acids 18

311 Diboronic acid B2(OH)4 as boron source 19

312 Synthesis of allylboronic acids and their isolation 20

32 Characterization of allylboroxine 22

33 Proposed mechanism for the allylic CminusOH borylation 24

34 Conclusions for the allylic CminusOH borylation 25

4 Allylboration of carbonyl compounds using allylboronic acids (Paper II-III) 26

41 Allylation of ketones by allylboronic acids 26

42 Stereoselectivity of α-hydroxy acids 31

43 Conclusions for allylboration of carbonyl compounds 32

ix

5 Synthesis of adjacent quaternary stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV) 33

51 Method development for the asymmetric allylboration of ketones helliphellip33

52 Stereocontrol in the asymmetric allylboration of ketone 35

53 Catalytic enantioselective allylboration of ketones 36

54 Proposed mechanism for the enantioselectivity of the allylboration of

ketones with allylboronic acids 38

541 Proposed models for enantioselectivity 40

542 Proposed catalytic cycle 41

55 Conclusions for the catalytic asymmetric allylboration 42

6 Allylboration of imines indoles and hydrazones (Paper V-VI) 43

61 Allylation of imines with allylboronic acids 43

62 Allylation of indoles with allylboronic acids 46

63 Allylation of acyl hydrazones with allylboronic acids 48

64 Mechanistic study and proposal for the allylation of aldimines 50

65 Proposed mechanism for the allylboration of hydrazones 52

66 Proposed mechanism for the allylboration of indoles 54

67 Conclusions for the allylboration of imines indoles and hydrazones 55

7 Concluding remarks 56

8 Acknowledgements 57

9 Summary in Swedish 58

10 Appendix A 59

11 References 60

x

xi

Abbreviations

Abbreviations are used in agreement with standards of the subject1 Addi-

tional non-standard or unconventional abbreviations that appear in this thesis

are listed below

B2pin2 bis(pinacolato)diboron

BINOL 11-bi-2-naphthol

Bpin pinacolato boron

BQ 14-benzoquinone

dba dibenzylideneacetone

DFT density functional theory

DMC dimethyl carbonate

dr diastereomeric ratio

er enantiomeric ratio

LA Lewis acid

L ligand (neutral)

L chiral ligand

MS molecular sieves

NOE nuclear Overhauser effect

PIFA phenyliodine bis(trifluoroacetate)

PIDA phenyliodonium diacetate

TFA trifluoroacetate

TS transition state

rt room temperature

X ligand (charged)

1

1 Introduction

The development of highly selective transformations is of fundamental

importance in modern organic chemistry Transition metal-catalysis is one of

the useful synthetic approaches to achieve this goal2 The allylation reaction

using allylboron reagents and other allyl sources is also an important ap-

proach to develop selective syntheses3

11 Palladium-catalyzed allylic CminusH acetoxylation

Transition metal-catalyzed substitution of allylic acetates and their ana-

logs is one of the most utilized and studied reactions4 An important method

to synthesize allylic acetates is Pd-catalyzed allylic CminusH functionalization5

Pioneering works by McMurry and Kocovsky6 and Aringkermark

7 have shown

that Pd(II)-catalyzed allylic acetoxylation of cyclic and acyclic olefins can

be achieved in the presence of acetic acid and benzoquinone (BQ) as oxidant

(Scheme 1) Mechanistic investigations by Baumlckvall8 and co-workers

indicated that a (π-allyl)palladium(II) intermediates are involved in the

process and that BQ serves as both oxidant and activator ligand in the

CminusOAc bond formation process

Scheme 1 Pd-catalyzed allylic CminusH acetoxylation reaction

7a

Recently the White9 and the Stahl

10 group independently reported new

methods for CminusH acetoxylation reactions using palladium catalysis The

latter group used O2 as an oxidant instead of BQ According to the mechanis-

tic studies by these authors the CminusH acetoxylation process take place via

Pd0 and Pd

II catalytic intermediates

Hypervalent iodine reagents were also employed as the principal compo-

nent in the allylic CminusH oxidation reactions5 11

For example Szaboacute and

co-workers11b

have reported the allylic CminusH acyloxylation reaction with

PhI(OAc)2 (2a) as the oxidant and source of OAc (Scheme 2) The use of a

2

palladium catalysts and hypervalent iodine reagents allowed an easy access

to allylic acetoxy and benzoyloxy compounds Based on the mechanistic

studies a PdIIPd

IV catalytic cycle was proposed when PhI(OAc)2 was used

as the oxidant

Scheme 2 Pd-catalyzed CminusH acetoxylation reaction reported by Szaboacute and co-

workers11b

In spite of the wide application of allylic CminusH acyloxylation reactions in

organic synthesis the stereoselective transformations of substituted cyclic

alkenes are limited Particularly the intermolecular diastereoselective CminusH

acyloxylation is still a challenge A new synthetic process for such a reaction

is presented in Chapter 2

12 Synthesis of allylboronates

Allylboronates are efficient reagents for regio- and stereoselective allyla-

tion of carbonyl compounds and some related functionalities3 12

Due to the

importance of allylboronates in synthetic organic chemistry there has been a

large interest in the development of new methods for the synthesis of these

reagents The classical synthetic procedures involve application of allyl-

Grignard and allyl-Li reagents13

However these methods have a limited

synthetic scope because of problems with the regioselective formation of the

allylboronates Palladium-catalyzed methods based on the substitution of allylic alcohol

derivatives have proven to be a versatile and relatively simple method to

obtain allylboronates The first process was reported by Miyaura and

co-workers14

(Scheme 3) In this process B2pin2 was used as the boron

source Although the regioselectivity of the reaction is excellent a drawback

of this process is the formation of varying amounts of homocoupling prod-

ucts

Scheme 3 Pd-catalyzed borylation of allylacetates

14

The Szaboacute group15

has expanded the substrate scope to include allylic

alcohols instead of allylic acetates (Scheme 4) It was also shown that

3

certain Pd(II) pincer complexes are more efficient than Pd(dba)2 In depth

mechanistic studies revealed that catalytic amounts of Lewis or Broslashnsted

acids are required in the reaction to activate the allylic alcohols for Pd-

catalyzed substitution16

The reaction is substantially accelerated in the pres-

ence of MeOH or other protic co-solvents

Scheme 4 Pd-catalyzed borylation of allylic alcohols

15c 15d

The Szaboacute group also developed palladium-catalyzed allylic C-H boryla-

tion methods17

These processes allowed for the synthesis of allylboronates

from readily available alkenes under oxidative conditions using BQ (1) or

the hypervalent iodonium salt

Ito Sawamura and their co-workers reported the regio- and stereoselec-

tive synthesis of allylboronates by Cu-catalyzed substitution of allyl

carbonates18

This method can also be extended to asymmetric catalysis for

the synthesis of enantioenriched allylboronates (Scheme 5)19

Scheme 5 Cu-catalyzed asymmetric borylation of allylcarbonates

19

Enantioselective synthesis of α-substituted allylboronates has been

reported by Hall and co-workers (Scheme 6)20

This method is based on

copper-catalyzed substitution of allylhalide substrates The chiral

allylboronates generated in this reaction were used for further transformation

without isolation

Scheme 6 Cu-catalyzed borylation reported by Hall and co-workers

20

Related Cu-catalyzed asymmetric synthesis of allylboronates have also

been independently reported by the groups of Hoveyda21

and McQuade22

Nickel-catalyzed stereospecific borylation of allylic acetates was developed

by Morken and co-workers23

The reaction is highly selective for the termi-

4

nal allylboronates (Scheme 7) The Morken group also developed palladi-

um-catalyzed enantioselective borylation methods for the synthesis of al-

lylboronates24

Scheme 7 Ni-catalyzed selective borylation of allylic acetates

23

Very recently Aggarwal and co-workers have reported a new method for

the preparation of enantioenriched allylboronates25

This so called ldquolithia-

tion-borylation methodrdquo involves homologation of vinyl boronates using

alkyl carbamates and butyllithium (BuLi) in the presence of (+)-sparteine

(Scheme 8)

Scheme 8 Synthesis of allylboronates by lithiation-borylation method

25b

As shown above synthesis of allylboron reagents has attracted large in-

terest in modern organic chemistry As a contribution to this field we devel-

oped a new method for the synthesis and isolation of allylboronic acids

which is presented in Chapter 3

13 Application of allylboronates in synthesis

Allylboronate reagents have been extensively used to synthesize numerous precursors for natural products and bioactive molecules

26

Addition of allylboronates to carbonyl and imine electrophiles is a well studied and documented reactions in synthetic organic chemistry

131 Stereoselective allylation of carbonyl compounds

Allylboration reactions of aldehydes have been widely applied for the ste-

reoselective synthesis of homoallylic alcohols3 After the discovery by Bub-

nov27

the reaction was further developed by Hoffmann28

Brown29

Roush30

and others Hoffmann and Brown carried out in depth mechanistic studies

which also explained the stereochemistry of the reaction Hoffman postulat-

ed that the reaction between allylboronates and aldehydes proceeds via a six-

5

membered cyclic TS similar to the Zimmerman-Traxler31

model (Scheme

9)28a 32

The high diastereoselectivity of the allylboration reaction is attributed to

an internal Lewis acid activation of the carbonyl functionality by the empty

p-orbital of boron

Scheme 9 Zimmerman-Traxler model to describe stereochemistry of allylboration

reaction

The addition of Lewis or Broslashnsted acids may accelerate the allylboration

of carbonyl compounds33

Hall and co-workers proposed that Lewis acids

coordinate to the lone pair of the boronate oxygen which renders the boron

atom more electron deficient (Scheme 10)33b 34

This mechanism for LA

and Broslashnsted acid activation was also confirmed by the DFT studies of

Houk and co-workers35

Scheme 10 Possible modes of Lewis acid activation for the allylboration

Allylboronates can also react with ketones yielding tertiary homoallylic

alcohols However the addition of allylboronates to ketones is much slower

than similar reactions with aldehydes Thus the selective allylation of

ketones with allylboronates often requires the use of catalysts36

In addition

most of the present methods for allylboration of ketones are limited to the

use of unsubstituted (parent) allylboronates or crotylboronates

132 Enantioselective allylation of carbonyl compounds

There are basically two main approaches for the asymmetric allylboration

of carbonyl compounds The first approach is the application of enantioen-

riched allylboronates performing chirality transfer and the second one is

6

asymmetric induction by using chiral catalyst One of the first asymmetric

allylboration reactions was reported by Roush and co-workers 13b 37

These

authors employed chiral auxiliaries attached to the boron atom (Scheme 11)

Diisopropyl tartrate (DIPT) proved to be a very efficient chiral auxiliary to

induce enantioselectivity

Scheme 11 Asymmetric allylation of aldehydes using chiral allylboronate

13b

A similar approach was reported by Soderquist and co-workers38

for the

asymmetric allylboration of aldehyde and ketones A bicyclic chiral auxilia-

ry on the boron atom was employed for highly diastereo- and enantioselec-

tive allylboration (Scheme 12)

Scheme 12 Diastereo-and enantioselective allylboration by chiral allylborane

38a

Enantiomerically pure TADDOL based allylboronates were developed by

Pietruszka and co-workers39

These reagents were used for chirality transfer

in allylboration of aldehydes (Scheme 13) The chiral auxiliary can be

recovered after the allylation by reduction with LiAlH4

Scheme 13 Asymmetric allylation of aldehyde using enantiopure allylboronate

39

Metal-catalyzed asymmetric synthesis of heterocyclic allylboronates was

described by Hall and co-workers40

These allylboronates were used in situ

for allylboration of aldehydes The key-step in synthesis of mefloquine was

performed using this method (Scheme 14)

7

Scheme 14 Asymmetric allylboration by cyclic allylboronates

40

Very recently Aggarwal and co-workers25b 41

reported an efficient

allylboration method using α-substituted enantioenriched allylboronates (see

also Scheme 8) The method is highly diastereo- and enantioselective In

addition the procedure is suitable for the synthesis of homoallylic alcohols

with two adjacent quaternary stereocenters (Scheme 15)

Scheme 15 Asymmetric allylation of ketone by α-substituted chiral allylboronate

25b

An alternative approach for the asymmetric allylboration of carbonyl

compounds involves the application of chiral catalysts Both Lewis and

Broslashnsted acids have been used for the asymmetric allylboration reactions

The first catalytic enantioselective allylboration reaction was reported by

Miyaura and co-workers (Scheme 16)33c

This reaction proceeded with a

high regio- and diastereoselectivity but the enantioselectivity was relatively

low

Scheme 16 Catalytic asymmetric allylboration of aldehyde

33c

Hall and co-workers42

reported a Sn-catalyzed asymmetric allylboration

reaction using allyl-Bpin as the allyl source A chiral diol was used as a lig-

and in this process which was supposed to coordinate to SnCl4 (Scheme 17)

8

Scheme 17 Tin-catalyzed asymmetric allylboration of aldehyde

42a

Asymmetric allylation of ketones was reported using chiral allylboronate

derived from BINOL compounds Chong and co-workers described the al-

lylation of ketones using 33-(CF3)2-BINOL boronate 3a (Scheme 18)43

The

reaction gave homoallylic alcohol product with a high level of enantioselec-

tivity

Scheme 18 Asymmetric allylation of ketone using BINOL-boronate

43

Catalytic methods have also been described to control both diastereo- and

enantioselectivity in the allylboration of ketones44

The first catalytic

enantioselective allylboration of ketones was developed by Shibasaki and

co-workers45

Broslashnsted acid such as BINOL derivatives44 46

was found to be

very efficient in the asymmetric allylboration reactions Schaus and

co-workers44

reported a method for asymmetric allylation of ketones using

isopropoxyboronate and catalytic amounts of Br2-BINOL 4a (Scheme 19)

Scheme 19 Catalytic asymmetric allylboration of ketone using Br2-BINOL

44a

These authors proposed a Zimmerman-Traxler type transition state to

rationalize the enantioselectivity in this reaction It has been also pointed out

that the substituent in BINOL (eg Br or CF3) has an important role for the

enantioselectivity of these reactions

Catalytic synthesis of homoallylic alcohols containing adjacent quater-

nary stereocenters has been a great challenge in synthetic organic chemistry

A new synthetic method for such reaction is presented in Section 52

9

133 Stereoselective allylation of imines

Homoallylic amine motifs occur in many natural products and biological-

ly relevant compounds47

One of the most common strategies for homoallylic

amine synthesis is the addition of allyl-metal reagents to imines48

The use of

allylboronate compounds for these reactions has emerged as an important

synthetic approach47

Allylboronates have a low toxicity high functional

group tolerance and the allylation of imines occurs with a high level of

selectivity

Stereoselective allylation of aldimines can be performed by

allylboronates in the presence of Lewis acid catalysts Batey and

co-workers49

reported the allylboration of N-toluenesulfonylimines using

crotyltrifluroboronate and BF3OEt2 (Scheme 20) The allylation was

proposed to proceed via the allyl-BF2 species which is generated from

allyl-BF3K

Scheme 20 Stereoselective allylation of imine by allyltrifluoroborate

49

Kobayashi and co-workers50

reported a three-component diastereoselec-

tive allylation reaction to synthesize homoallylic primary amines (Scheme

21) In addition several useful methods for asymmetric allylboration of

imines25b 51

using allylboronates can also be found in literature

Scheme 21 Synthesis of homoallylic amine using multicomponent method

50

Allylboration of acylhydrazones have also proven to be a very useful

reaction for the synthesis of homoallylic amine derivatives However the

allylation of acylhydrazones by allylboronates requires the application of

metal catalysts52

An indium-catalyzed reaction for the allylation of N-

acylhydrazone was reported by Kobayashi and co-workers (Scheme 22)52a

It

has been proposed that indium undergoes a transmetallation with allyl-Bpin

to form an active allyl-indium species which then added to the hydrazone

10

Scheme 22 Indium-catalyzed allylation of acylhydrazone

52a

We have developed a stereoselective method for allylation of imines and

acylhydrazones using allylboronic acids These results are summarized in

Chapter 6

11

2 Pd-catalyzed stereoselective allylic CminusH

trifluoroacetoxylation (Paper I)

As mentioned in the introduction transition metal-catalyzed CminusH bond activation methods have attracted increasing interest in organic synthesis

53

Using these methods multistep synthesis for prefunctionalization of the or-ganic substrates is not necessary In addition the waste production of the reaction can be reduced as the new functional group can be installed by re-placement of hydrogen

54 Palladium-catalyzed allylic CminusH bond activation is

one of the oldest and most versatile CminusH functionalization method (Section 11)

55 In this reaction (as in CminusH activation based processes in general) the

greatest challenge is the control of the regio- and stereoselectivity of the process

Stereodefined allylic acetates are very important precursors for regio- and stereoselective palladium-catalyzed allylic substitution reactions

56 Although

many regioselective allylic CminusH functionalization methods have been re-ported there are few reports on stereoselective allylic CminusH acetoxylation

7a

Most of these studies are intramolecular CminusH acyloxylation reactions For example a stereoselective allylic CminusH acetoxylation method has been re-ported by White and co-workers (Scheme 23) Intramolecular selectivity control allowed macrocyclization

57 and straightforward synthesis of anti-14-

dioxan-2-ones58

from simple olefins using Pd(II)sulfoxide catalysis Baumlck-vall and co-workers

59 have also developed several methods for the synthesis

of allylacetoxy compounds based on palladium-catalyzed intramolecular oxidative carbocyclization

Scheme 23 Stereoselective intramolecular CminusH oxidation reported by White and

co-workers58

12

21 Development of selective intermolecular allylic CminusH trifluoroacetoxylation

As our group previously developed a useful allylic CminusH acetoxylation

method based on using PhI(OAc)2 (2a) (see Section 11) as oxidant and ace-

tate source we envisioned that PhI(OCOCF3)2 (2b) can also be used in this

type of reaction to introduce a trifluoroacetate group at the allylic position of

alkenes Allylic trifluoroacetates are more reactive than allylic acetates in

transition metal-catalyzed substitutions60

and therefore an easy access to

these compounds is desirable As far as we know selective allylic CminusH tri-

fluoroacetoxylation has not been reported in the literature

In the early stage of development and optimization we employed car-

boxylated alkene 6a as our model substrate as it gave a high yield and ex-

hibited high selectivity in the Pd-catalyzed CminusH acetoxylation with 2a11b

However PhI(OCOCF3)2 (2b) is most likely a stronger oxidant than

PhI(OAc)2 (2a) and therefore we could not use oxidation sensitive solvents

such as THF or DMSO In addition the conjugated acid of the trifluoroace-

tate ion (the nucleophile) is a strong acid and therefore trifluoroacetic acid

could not be used as the solvent either After short optimization we have

found that dimethyl carbonate (DMC) is an excellent solvent for all reaction

components and it is not oxidized by PIFA We have found that the isolated

yields are higher when LiOCOCF3 is used as additive Under these condi-

tions the reaction could be performed with various functionalized alkenes

(Table 1)

13

Table 1 Pd-catalyzed allylic CminusH trifluoroacetoxylation of acyclic olefinsa

Both Pd(OAc)2 (5b) and Pd(OCOCF3)2 (5c) were equally efficient as cat-

alyst in the reaction So we decided to use 5b in the present synthetic method

as it is less expensive than 5c Not only terminal (6a) but internal alkenes

6b-c could also be used for trifluoroacetoxylation with high selectivity Oth-

er alkenes with electron withdrawing substituents such as 6d-e could also be

smoothly trifluoroacetoxylated Substrates without electron-withdrawing

groups gave intractable mixtures of trifluoroacetoxylated products For com-

pounds with long alkyl chain oxidation of the double bond occurred while in

the case of electron donating substituents mainly oxidation of the double

bond occurred together with other processes

14

Table 2 Stereoselective allylic CminusH trifluoroacetoxylation of cyclic alkenesa

Not only acyclic alkenes but cyclic alkenes could also be employed for

the trifluoroacetoxylation reaction Monosubstituted cyclic alkenes reacted

with a remarkably high selectivity (Table 2) The reaction conditions were

very similar to the trifluoroacetoxylation of acyclic substrates (Table 1) but

in order to get this high stereoselectivity the reactions had to be conducted

at 0 degC This is below the freezing point of DMC therefore the reaction me-

dium was diluted with DCM to avoid freezing of the reaction mixture The

yields with LiOCOCF3 were as high as in its absence therefore we did not

use this additive in the trifluoroacetoxylation of cyclic substrates

Considering the number of possible regio- and stereoisomers a mixture

of six allylic trifluoroacetate products could be expected Yet in most cases

we obtained a single diastereomer with very high regioselectivity (Table 2

entries 1-2 and 4-5) The major regioisomer in all cases was the 14-

substituted product (7f-j) with anti diastereoselectivity and the minor prod-

uct is the regioisomer of the same diastereomer The stereochemistry of the

major isomers was assigned based on NOE experiments

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

1 The ACS Style Guide 3rd ed Oxford University Press New York 2006

2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

ix

5 Synthesis of adjacent quaternary stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV) 33

51 Method development for the asymmetric allylboration of ketones helliphellip33

52 Stereocontrol in the asymmetric allylboration of ketone 35

53 Catalytic enantioselective allylboration of ketones 36

54 Proposed mechanism for the enantioselectivity of the allylboration of

ketones with allylboronic acids 38

541 Proposed models for enantioselectivity 40

542 Proposed catalytic cycle 41

55 Conclusions for the catalytic asymmetric allylboration 42

6 Allylboration of imines indoles and hydrazones (Paper V-VI) 43

61 Allylation of imines with allylboronic acids 43

62 Allylation of indoles with allylboronic acids 46

63 Allylation of acyl hydrazones with allylboronic acids 48

64 Mechanistic study and proposal for the allylation of aldimines 50

65 Proposed mechanism for the allylboration of hydrazones 52

66 Proposed mechanism for the allylboration of indoles 54

67 Conclusions for the allylboration of imines indoles and hydrazones 55

7 Concluding remarks 56

8 Acknowledgements 57

9 Summary in Swedish 58

10 Appendix A 59

11 References 60

x

xi

Abbreviations

Abbreviations are used in agreement with standards of the subject1 Addi-

tional non-standard or unconventional abbreviations that appear in this thesis

are listed below

B2pin2 bis(pinacolato)diboron

BINOL 11-bi-2-naphthol

Bpin pinacolato boron

BQ 14-benzoquinone

dba dibenzylideneacetone

DFT density functional theory

DMC dimethyl carbonate

dr diastereomeric ratio

er enantiomeric ratio

LA Lewis acid

L ligand (neutral)

L chiral ligand

MS molecular sieves

NOE nuclear Overhauser effect

PIFA phenyliodine bis(trifluoroacetate)

PIDA phenyliodonium diacetate

TFA trifluoroacetate

TS transition state

rt room temperature

X ligand (charged)

1

1 Introduction

The development of highly selective transformations is of fundamental

importance in modern organic chemistry Transition metal-catalysis is one of

the useful synthetic approaches to achieve this goal2 The allylation reaction

using allylboron reagents and other allyl sources is also an important ap-

proach to develop selective syntheses3

11 Palladium-catalyzed allylic CminusH acetoxylation

Transition metal-catalyzed substitution of allylic acetates and their ana-

logs is one of the most utilized and studied reactions4 An important method

to synthesize allylic acetates is Pd-catalyzed allylic CminusH functionalization5

Pioneering works by McMurry and Kocovsky6 and Aringkermark

7 have shown

that Pd(II)-catalyzed allylic acetoxylation of cyclic and acyclic olefins can

be achieved in the presence of acetic acid and benzoquinone (BQ) as oxidant

(Scheme 1) Mechanistic investigations by Baumlckvall8 and co-workers

indicated that a (π-allyl)palladium(II) intermediates are involved in the

process and that BQ serves as both oxidant and activator ligand in the

CminusOAc bond formation process

Scheme 1 Pd-catalyzed allylic CminusH acetoxylation reaction

7a

Recently the White9 and the Stahl

10 group independently reported new

methods for CminusH acetoxylation reactions using palladium catalysis The

latter group used O2 as an oxidant instead of BQ According to the mechanis-

tic studies by these authors the CminusH acetoxylation process take place via

Pd0 and Pd

II catalytic intermediates

Hypervalent iodine reagents were also employed as the principal compo-

nent in the allylic CminusH oxidation reactions5 11

For example Szaboacute and

co-workers11b

have reported the allylic CminusH acyloxylation reaction with

PhI(OAc)2 (2a) as the oxidant and source of OAc (Scheme 2) The use of a

2

palladium catalysts and hypervalent iodine reagents allowed an easy access

to allylic acetoxy and benzoyloxy compounds Based on the mechanistic

studies a PdIIPd

IV catalytic cycle was proposed when PhI(OAc)2 was used

as the oxidant

Scheme 2 Pd-catalyzed CminusH acetoxylation reaction reported by Szaboacute and co-

workers11b

In spite of the wide application of allylic CminusH acyloxylation reactions in

organic synthesis the stereoselective transformations of substituted cyclic

alkenes are limited Particularly the intermolecular diastereoselective CminusH

acyloxylation is still a challenge A new synthetic process for such a reaction

is presented in Chapter 2

12 Synthesis of allylboronates

Allylboronates are efficient reagents for regio- and stereoselective allyla-

tion of carbonyl compounds and some related functionalities3 12

Due to the

importance of allylboronates in synthetic organic chemistry there has been a

large interest in the development of new methods for the synthesis of these

reagents The classical synthetic procedures involve application of allyl-

Grignard and allyl-Li reagents13

However these methods have a limited

synthetic scope because of problems with the regioselective formation of the

allylboronates Palladium-catalyzed methods based on the substitution of allylic alcohol

derivatives have proven to be a versatile and relatively simple method to

obtain allylboronates The first process was reported by Miyaura and

co-workers14

(Scheme 3) In this process B2pin2 was used as the boron

source Although the regioselectivity of the reaction is excellent a drawback

of this process is the formation of varying amounts of homocoupling prod-

ucts

Scheme 3 Pd-catalyzed borylation of allylacetates

14

The Szaboacute group15

has expanded the substrate scope to include allylic

alcohols instead of allylic acetates (Scheme 4) It was also shown that

3

certain Pd(II) pincer complexes are more efficient than Pd(dba)2 In depth

mechanistic studies revealed that catalytic amounts of Lewis or Broslashnsted

acids are required in the reaction to activate the allylic alcohols for Pd-

catalyzed substitution16

The reaction is substantially accelerated in the pres-

ence of MeOH or other protic co-solvents

Scheme 4 Pd-catalyzed borylation of allylic alcohols

15c 15d

The Szaboacute group also developed palladium-catalyzed allylic C-H boryla-

tion methods17

These processes allowed for the synthesis of allylboronates

from readily available alkenes under oxidative conditions using BQ (1) or

the hypervalent iodonium salt

Ito Sawamura and their co-workers reported the regio- and stereoselec-

tive synthesis of allylboronates by Cu-catalyzed substitution of allyl

carbonates18

This method can also be extended to asymmetric catalysis for

the synthesis of enantioenriched allylboronates (Scheme 5)19

Scheme 5 Cu-catalyzed asymmetric borylation of allylcarbonates

19

Enantioselective synthesis of α-substituted allylboronates has been

reported by Hall and co-workers (Scheme 6)20

This method is based on

copper-catalyzed substitution of allylhalide substrates The chiral

allylboronates generated in this reaction were used for further transformation

without isolation

Scheme 6 Cu-catalyzed borylation reported by Hall and co-workers

20

Related Cu-catalyzed asymmetric synthesis of allylboronates have also

been independently reported by the groups of Hoveyda21

and McQuade22

Nickel-catalyzed stereospecific borylation of allylic acetates was developed

by Morken and co-workers23

The reaction is highly selective for the termi-

4

nal allylboronates (Scheme 7) The Morken group also developed palladi-

um-catalyzed enantioselective borylation methods for the synthesis of al-

lylboronates24

Scheme 7 Ni-catalyzed selective borylation of allylic acetates

23

Very recently Aggarwal and co-workers have reported a new method for

the preparation of enantioenriched allylboronates25

This so called ldquolithia-

tion-borylation methodrdquo involves homologation of vinyl boronates using

alkyl carbamates and butyllithium (BuLi) in the presence of (+)-sparteine

(Scheme 8)

Scheme 8 Synthesis of allylboronates by lithiation-borylation method

25b

As shown above synthesis of allylboron reagents has attracted large in-

terest in modern organic chemistry As a contribution to this field we devel-

oped a new method for the synthesis and isolation of allylboronic acids

which is presented in Chapter 3

13 Application of allylboronates in synthesis

Allylboronate reagents have been extensively used to synthesize numerous precursors for natural products and bioactive molecules

26

Addition of allylboronates to carbonyl and imine electrophiles is a well studied and documented reactions in synthetic organic chemistry

131 Stereoselective allylation of carbonyl compounds

Allylboration reactions of aldehydes have been widely applied for the ste-

reoselective synthesis of homoallylic alcohols3 After the discovery by Bub-

nov27

the reaction was further developed by Hoffmann28

Brown29

Roush30

and others Hoffmann and Brown carried out in depth mechanistic studies

which also explained the stereochemistry of the reaction Hoffman postulat-

ed that the reaction between allylboronates and aldehydes proceeds via a six-

5

membered cyclic TS similar to the Zimmerman-Traxler31

model (Scheme

9)28a 32

The high diastereoselectivity of the allylboration reaction is attributed to

an internal Lewis acid activation of the carbonyl functionality by the empty

p-orbital of boron

Scheme 9 Zimmerman-Traxler model to describe stereochemistry of allylboration

reaction

The addition of Lewis or Broslashnsted acids may accelerate the allylboration

of carbonyl compounds33

Hall and co-workers proposed that Lewis acids

coordinate to the lone pair of the boronate oxygen which renders the boron

atom more electron deficient (Scheme 10)33b 34

This mechanism for LA

and Broslashnsted acid activation was also confirmed by the DFT studies of

Houk and co-workers35

Scheme 10 Possible modes of Lewis acid activation for the allylboration

Allylboronates can also react with ketones yielding tertiary homoallylic

alcohols However the addition of allylboronates to ketones is much slower

than similar reactions with aldehydes Thus the selective allylation of

ketones with allylboronates often requires the use of catalysts36

In addition

most of the present methods for allylboration of ketones are limited to the

use of unsubstituted (parent) allylboronates or crotylboronates

132 Enantioselective allylation of carbonyl compounds

There are basically two main approaches for the asymmetric allylboration

of carbonyl compounds The first approach is the application of enantioen-

riched allylboronates performing chirality transfer and the second one is

6

asymmetric induction by using chiral catalyst One of the first asymmetric

allylboration reactions was reported by Roush and co-workers 13b 37

These

authors employed chiral auxiliaries attached to the boron atom (Scheme 11)

Diisopropyl tartrate (DIPT) proved to be a very efficient chiral auxiliary to

induce enantioselectivity

Scheme 11 Asymmetric allylation of aldehydes using chiral allylboronate

13b

A similar approach was reported by Soderquist and co-workers38

for the

asymmetric allylboration of aldehyde and ketones A bicyclic chiral auxilia-

ry on the boron atom was employed for highly diastereo- and enantioselec-

tive allylboration (Scheme 12)

Scheme 12 Diastereo-and enantioselective allylboration by chiral allylborane

38a

Enantiomerically pure TADDOL based allylboronates were developed by

Pietruszka and co-workers39

These reagents were used for chirality transfer

in allylboration of aldehydes (Scheme 13) The chiral auxiliary can be

recovered after the allylation by reduction with LiAlH4

Scheme 13 Asymmetric allylation of aldehyde using enantiopure allylboronate

39

Metal-catalyzed asymmetric synthesis of heterocyclic allylboronates was

described by Hall and co-workers40

These allylboronates were used in situ

for allylboration of aldehydes The key-step in synthesis of mefloquine was

performed using this method (Scheme 14)

7

Scheme 14 Asymmetric allylboration by cyclic allylboronates

40

Very recently Aggarwal and co-workers25b 41

reported an efficient

allylboration method using α-substituted enantioenriched allylboronates (see

also Scheme 8) The method is highly diastereo- and enantioselective In

addition the procedure is suitable for the synthesis of homoallylic alcohols

with two adjacent quaternary stereocenters (Scheme 15)

Scheme 15 Asymmetric allylation of ketone by α-substituted chiral allylboronate

25b

An alternative approach for the asymmetric allylboration of carbonyl

compounds involves the application of chiral catalysts Both Lewis and

Broslashnsted acids have been used for the asymmetric allylboration reactions

The first catalytic enantioselective allylboration reaction was reported by

Miyaura and co-workers (Scheme 16)33c

This reaction proceeded with a

high regio- and diastereoselectivity but the enantioselectivity was relatively

low

Scheme 16 Catalytic asymmetric allylboration of aldehyde

33c

Hall and co-workers42

reported a Sn-catalyzed asymmetric allylboration

reaction using allyl-Bpin as the allyl source A chiral diol was used as a lig-

and in this process which was supposed to coordinate to SnCl4 (Scheme 17)

8

Scheme 17 Tin-catalyzed asymmetric allylboration of aldehyde

42a

Asymmetric allylation of ketones was reported using chiral allylboronate

derived from BINOL compounds Chong and co-workers described the al-

lylation of ketones using 33-(CF3)2-BINOL boronate 3a (Scheme 18)43

The

reaction gave homoallylic alcohol product with a high level of enantioselec-

tivity

Scheme 18 Asymmetric allylation of ketone using BINOL-boronate

43

Catalytic methods have also been described to control both diastereo- and

enantioselectivity in the allylboration of ketones44

The first catalytic

enantioselective allylboration of ketones was developed by Shibasaki and

co-workers45

Broslashnsted acid such as BINOL derivatives44 46

was found to be

very efficient in the asymmetric allylboration reactions Schaus and

co-workers44

reported a method for asymmetric allylation of ketones using

isopropoxyboronate and catalytic amounts of Br2-BINOL 4a (Scheme 19)

Scheme 19 Catalytic asymmetric allylboration of ketone using Br2-BINOL

44a

These authors proposed a Zimmerman-Traxler type transition state to

rationalize the enantioselectivity in this reaction It has been also pointed out

that the substituent in BINOL (eg Br or CF3) has an important role for the

enantioselectivity of these reactions

Catalytic synthesis of homoallylic alcohols containing adjacent quater-

nary stereocenters has been a great challenge in synthetic organic chemistry

A new synthetic method for such reaction is presented in Section 52

9

133 Stereoselective allylation of imines

Homoallylic amine motifs occur in many natural products and biological-

ly relevant compounds47

One of the most common strategies for homoallylic

amine synthesis is the addition of allyl-metal reagents to imines48

The use of

allylboronate compounds for these reactions has emerged as an important

synthetic approach47

Allylboronates have a low toxicity high functional

group tolerance and the allylation of imines occurs with a high level of

selectivity

Stereoselective allylation of aldimines can be performed by

allylboronates in the presence of Lewis acid catalysts Batey and

co-workers49

reported the allylboration of N-toluenesulfonylimines using

crotyltrifluroboronate and BF3OEt2 (Scheme 20) The allylation was

proposed to proceed via the allyl-BF2 species which is generated from

allyl-BF3K

Scheme 20 Stereoselective allylation of imine by allyltrifluoroborate

49

Kobayashi and co-workers50

reported a three-component diastereoselec-

tive allylation reaction to synthesize homoallylic primary amines (Scheme

21) In addition several useful methods for asymmetric allylboration of

imines25b 51

using allylboronates can also be found in literature

Scheme 21 Synthesis of homoallylic amine using multicomponent method

50

Allylboration of acylhydrazones have also proven to be a very useful

reaction for the synthesis of homoallylic amine derivatives However the

allylation of acylhydrazones by allylboronates requires the application of

metal catalysts52

An indium-catalyzed reaction for the allylation of N-

acylhydrazone was reported by Kobayashi and co-workers (Scheme 22)52a

It

has been proposed that indium undergoes a transmetallation with allyl-Bpin

to form an active allyl-indium species which then added to the hydrazone

10

Scheme 22 Indium-catalyzed allylation of acylhydrazone

52a

We have developed a stereoselective method for allylation of imines and

acylhydrazones using allylboronic acids These results are summarized in

Chapter 6

11

2 Pd-catalyzed stereoselective allylic CminusH

trifluoroacetoxylation (Paper I)

As mentioned in the introduction transition metal-catalyzed CminusH bond activation methods have attracted increasing interest in organic synthesis

53

Using these methods multistep synthesis for prefunctionalization of the or-ganic substrates is not necessary In addition the waste production of the reaction can be reduced as the new functional group can be installed by re-placement of hydrogen

54 Palladium-catalyzed allylic CminusH bond activation is

one of the oldest and most versatile CminusH functionalization method (Section 11)

55 In this reaction (as in CminusH activation based processes in general) the

greatest challenge is the control of the regio- and stereoselectivity of the process

Stereodefined allylic acetates are very important precursors for regio- and stereoselective palladium-catalyzed allylic substitution reactions

56 Although

many regioselective allylic CminusH functionalization methods have been re-ported there are few reports on stereoselective allylic CminusH acetoxylation

7a

Most of these studies are intramolecular CminusH acyloxylation reactions For example a stereoselective allylic CminusH acetoxylation method has been re-ported by White and co-workers (Scheme 23) Intramolecular selectivity control allowed macrocyclization

57 and straightforward synthesis of anti-14-

dioxan-2-ones58

from simple olefins using Pd(II)sulfoxide catalysis Baumlck-vall and co-workers

59 have also developed several methods for the synthesis

of allylacetoxy compounds based on palladium-catalyzed intramolecular oxidative carbocyclization

Scheme 23 Stereoselective intramolecular CminusH oxidation reported by White and

co-workers58

12

21 Development of selective intermolecular allylic CminusH trifluoroacetoxylation

As our group previously developed a useful allylic CminusH acetoxylation

method based on using PhI(OAc)2 (2a) (see Section 11) as oxidant and ace-

tate source we envisioned that PhI(OCOCF3)2 (2b) can also be used in this

type of reaction to introduce a trifluoroacetate group at the allylic position of

alkenes Allylic trifluoroacetates are more reactive than allylic acetates in

transition metal-catalyzed substitutions60

and therefore an easy access to

these compounds is desirable As far as we know selective allylic CminusH tri-

fluoroacetoxylation has not been reported in the literature

In the early stage of development and optimization we employed car-

boxylated alkene 6a as our model substrate as it gave a high yield and ex-

hibited high selectivity in the Pd-catalyzed CminusH acetoxylation with 2a11b

However PhI(OCOCF3)2 (2b) is most likely a stronger oxidant than

PhI(OAc)2 (2a) and therefore we could not use oxidation sensitive solvents

such as THF or DMSO In addition the conjugated acid of the trifluoroace-

tate ion (the nucleophile) is a strong acid and therefore trifluoroacetic acid

could not be used as the solvent either After short optimization we have

found that dimethyl carbonate (DMC) is an excellent solvent for all reaction

components and it is not oxidized by PIFA We have found that the isolated

yields are higher when LiOCOCF3 is used as additive Under these condi-

tions the reaction could be performed with various functionalized alkenes

(Table 1)

13

Table 1 Pd-catalyzed allylic CminusH trifluoroacetoxylation of acyclic olefinsa

Both Pd(OAc)2 (5b) and Pd(OCOCF3)2 (5c) were equally efficient as cat-

alyst in the reaction So we decided to use 5b in the present synthetic method

as it is less expensive than 5c Not only terminal (6a) but internal alkenes

6b-c could also be used for trifluoroacetoxylation with high selectivity Oth-

er alkenes with electron withdrawing substituents such as 6d-e could also be

smoothly trifluoroacetoxylated Substrates without electron-withdrawing

groups gave intractable mixtures of trifluoroacetoxylated products For com-

pounds with long alkyl chain oxidation of the double bond occurred while in

the case of electron donating substituents mainly oxidation of the double

bond occurred together with other processes

14

Table 2 Stereoselective allylic CminusH trifluoroacetoxylation of cyclic alkenesa

Not only acyclic alkenes but cyclic alkenes could also be employed for

the trifluoroacetoxylation reaction Monosubstituted cyclic alkenes reacted

with a remarkably high selectivity (Table 2) The reaction conditions were

very similar to the trifluoroacetoxylation of acyclic substrates (Table 1) but

in order to get this high stereoselectivity the reactions had to be conducted

at 0 degC This is below the freezing point of DMC therefore the reaction me-

dium was diluted with DCM to avoid freezing of the reaction mixture The

yields with LiOCOCF3 were as high as in its absence therefore we did not

use this additive in the trifluoroacetoxylation of cyclic substrates

Considering the number of possible regio- and stereoisomers a mixture

of six allylic trifluoroacetate products could be expected Yet in most cases

we obtained a single diastereomer with very high regioselectivity (Table 2

entries 1-2 and 4-5) The major regioisomer in all cases was the 14-

substituted product (7f-j) with anti diastereoselectivity and the minor prod-

uct is the regioisomer of the same diastereomer The stereochemistry of the

major isomers was assigned based on NOE experiments

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

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3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

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12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

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19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

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1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

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91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

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94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

x

xi

Abbreviations

Abbreviations are used in agreement with standards of the subject1 Addi-

tional non-standard or unconventional abbreviations that appear in this thesis

are listed below

B2pin2 bis(pinacolato)diboron

BINOL 11-bi-2-naphthol

Bpin pinacolato boron

BQ 14-benzoquinone

dba dibenzylideneacetone

DFT density functional theory

DMC dimethyl carbonate

dr diastereomeric ratio

er enantiomeric ratio

LA Lewis acid

L ligand (neutral)

L chiral ligand

MS molecular sieves

NOE nuclear Overhauser effect

PIFA phenyliodine bis(trifluoroacetate)

PIDA phenyliodonium diacetate

TFA trifluoroacetate

TS transition state

rt room temperature

X ligand (charged)

1

1 Introduction

The development of highly selective transformations is of fundamental

importance in modern organic chemistry Transition metal-catalysis is one of

the useful synthetic approaches to achieve this goal2 The allylation reaction

using allylboron reagents and other allyl sources is also an important ap-

proach to develop selective syntheses3

11 Palladium-catalyzed allylic CminusH acetoxylation

Transition metal-catalyzed substitution of allylic acetates and their ana-

logs is one of the most utilized and studied reactions4 An important method

to synthesize allylic acetates is Pd-catalyzed allylic CminusH functionalization5

Pioneering works by McMurry and Kocovsky6 and Aringkermark

7 have shown

that Pd(II)-catalyzed allylic acetoxylation of cyclic and acyclic olefins can

be achieved in the presence of acetic acid and benzoquinone (BQ) as oxidant

(Scheme 1) Mechanistic investigations by Baumlckvall8 and co-workers

indicated that a (π-allyl)palladium(II) intermediates are involved in the

process and that BQ serves as both oxidant and activator ligand in the

CminusOAc bond formation process

Scheme 1 Pd-catalyzed allylic CminusH acetoxylation reaction

7a

Recently the White9 and the Stahl

10 group independently reported new

methods for CminusH acetoxylation reactions using palladium catalysis The

latter group used O2 as an oxidant instead of BQ According to the mechanis-

tic studies by these authors the CminusH acetoxylation process take place via

Pd0 and Pd

II catalytic intermediates

Hypervalent iodine reagents were also employed as the principal compo-

nent in the allylic CminusH oxidation reactions5 11

For example Szaboacute and

co-workers11b

have reported the allylic CminusH acyloxylation reaction with

PhI(OAc)2 (2a) as the oxidant and source of OAc (Scheme 2) The use of a

2

palladium catalysts and hypervalent iodine reagents allowed an easy access

to allylic acetoxy and benzoyloxy compounds Based on the mechanistic

studies a PdIIPd

IV catalytic cycle was proposed when PhI(OAc)2 was used

as the oxidant

Scheme 2 Pd-catalyzed CminusH acetoxylation reaction reported by Szaboacute and co-

workers11b

In spite of the wide application of allylic CminusH acyloxylation reactions in

organic synthesis the stereoselective transformations of substituted cyclic

alkenes are limited Particularly the intermolecular diastereoselective CminusH

acyloxylation is still a challenge A new synthetic process for such a reaction

is presented in Chapter 2

12 Synthesis of allylboronates

Allylboronates are efficient reagents for regio- and stereoselective allyla-

tion of carbonyl compounds and some related functionalities3 12

Due to the

importance of allylboronates in synthetic organic chemistry there has been a

large interest in the development of new methods for the synthesis of these

reagents The classical synthetic procedures involve application of allyl-

Grignard and allyl-Li reagents13

However these methods have a limited

synthetic scope because of problems with the regioselective formation of the

allylboronates Palladium-catalyzed methods based on the substitution of allylic alcohol

derivatives have proven to be a versatile and relatively simple method to

obtain allylboronates The first process was reported by Miyaura and

co-workers14

(Scheme 3) In this process B2pin2 was used as the boron

source Although the regioselectivity of the reaction is excellent a drawback

of this process is the formation of varying amounts of homocoupling prod-

ucts

Scheme 3 Pd-catalyzed borylation of allylacetates

14

The Szaboacute group15

has expanded the substrate scope to include allylic

alcohols instead of allylic acetates (Scheme 4) It was also shown that

3

certain Pd(II) pincer complexes are more efficient than Pd(dba)2 In depth

mechanistic studies revealed that catalytic amounts of Lewis or Broslashnsted

acids are required in the reaction to activate the allylic alcohols for Pd-

catalyzed substitution16

The reaction is substantially accelerated in the pres-

ence of MeOH or other protic co-solvents

Scheme 4 Pd-catalyzed borylation of allylic alcohols

15c 15d

The Szaboacute group also developed palladium-catalyzed allylic C-H boryla-

tion methods17

These processes allowed for the synthesis of allylboronates

from readily available alkenes under oxidative conditions using BQ (1) or

the hypervalent iodonium salt

Ito Sawamura and their co-workers reported the regio- and stereoselec-

tive synthesis of allylboronates by Cu-catalyzed substitution of allyl

carbonates18

This method can also be extended to asymmetric catalysis for

the synthesis of enantioenriched allylboronates (Scheme 5)19

Scheme 5 Cu-catalyzed asymmetric borylation of allylcarbonates

19

Enantioselective synthesis of α-substituted allylboronates has been

reported by Hall and co-workers (Scheme 6)20

This method is based on

copper-catalyzed substitution of allylhalide substrates The chiral

allylboronates generated in this reaction were used for further transformation

without isolation

Scheme 6 Cu-catalyzed borylation reported by Hall and co-workers

20

Related Cu-catalyzed asymmetric synthesis of allylboronates have also

been independently reported by the groups of Hoveyda21

and McQuade22

Nickel-catalyzed stereospecific borylation of allylic acetates was developed

by Morken and co-workers23

The reaction is highly selective for the termi-

4

nal allylboronates (Scheme 7) The Morken group also developed palladi-

um-catalyzed enantioselective borylation methods for the synthesis of al-

lylboronates24

Scheme 7 Ni-catalyzed selective borylation of allylic acetates

23

Very recently Aggarwal and co-workers have reported a new method for

the preparation of enantioenriched allylboronates25

This so called ldquolithia-

tion-borylation methodrdquo involves homologation of vinyl boronates using

alkyl carbamates and butyllithium (BuLi) in the presence of (+)-sparteine

(Scheme 8)

Scheme 8 Synthesis of allylboronates by lithiation-borylation method

25b

As shown above synthesis of allylboron reagents has attracted large in-

terest in modern organic chemistry As a contribution to this field we devel-

oped a new method for the synthesis and isolation of allylboronic acids

which is presented in Chapter 3

13 Application of allylboronates in synthesis

Allylboronate reagents have been extensively used to synthesize numerous precursors for natural products and bioactive molecules

26

Addition of allylboronates to carbonyl and imine electrophiles is a well studied and documented reactions in synthetic organic chemistry

131 Stereoselective allylation of carbonyl compounds

Allylboration reactions of aldehydes have been widely applied for the ste-

reoselective synthesis of homoallylic alcohols3 After the discovery by Bub-

nov27

the reaction was further developed by Hoffmann28

Brown29

Roush30

and others Hoffmann and Brown carried out in depth mechanistic studies

which also explained the stereochemistry of the reaction Hoffman postulat-

ed that the reaction between allylboronates and aldehydes proceeds via a six-

5

membered cyclic TS similar to the Zimmerman-Traxler31

model (Scheme

9)28a 32

The high diastereoselectivity of the allylboration reaction is attributed to

an internal Lewis acid activation of the carbonyl functionality by the empty

p-orbital of boron

Scheme 9 Zimmerman-Traxler model to describe stereochemistry of allylboration

reaction

The addition of Lewis or Broslashnsted acids may accelerate the allylboration

of carbonyl compounds33

Hall and co-workers proposed that Lewis acids

coordinate to the lone pair of the boronate oxygen which renders the boron

atom more electron deficient (Scheme 10)33b 34

This mechanism for LA

and Broslashnsted acid activation was also confirmed by the DFT studies of

Houk and co-workers35

Scheme 10 Possible modes of Lewis acid activation for the allylboration

Allylboronates can also react with ketones yielding tertiary homoallylic

alcohols However the addition of allylboronates to ketones is much slower

than similar reactions with aldehydes Thus the selective allylation of

ketones with allylboronates often requires the use of catalysts36

In addition

most of the present methods for allylboration of ketones are limited to the

use of unsubstituted (parent) allylboronates or crotylboronates

132 Enantioselective allylation of carbonyl compounds

There are basically two main approaches for the asymmetric allylboration

of carbonyl compounds The first approach is the application of enantioen-

riched allylboronates performing chirality transfer and the second one is

6

asymmetric induction by using chiral catalyst One of the first asymmetric

allylboration reactions was reported by Roush and co-workers 13b 37

These

authors employed chiral auxiliaries attached to the boron atom (Scheme 11)

Diisopropyl tartrate (DIPT) proved to be a very efficient chiral auxiliary to

induce enantioselectivity

Scheme 11 Asymmetric allylation of aldehydes using chiral allylboronate

13b

A similar approach was reported by Soderquist and co-workers38

for the

asymmetric allylboration of aldehyde and ketones A bicyclic chiral auxilia-

ry on the boron atom was employed for highly diastereo- and enantioselec-

tive allylboration (Scheme 12)

Scheme 12 Diastereo-and enantioselective allylboration by chiral allylborane

38a

Enantiomerically pure TADDOL based allylboronates were developed by

Pietruszka and co-workers39

These reagents were used for chirality transfer

in allylboration of aldehydes (Scheme 13) The chiral auxiliary can be

recovered after the allylation by reduction with LiAlH4

Scheme 13 Asymmetric allylation of aldehyde using enantiopure allylboronate

39

Metal-catalyzed asymmetric synthesis of heterocyclic allylboronates was

described by Hall and co-workers40

These allylboronates were used in situ

for allylboration of aldehydes The key-step in synthesis of mefloquine was

performed using this method (Scheme 14)

7

Scheme 14 Asymmetric allylboration by cyclic allylboronates

40

Very recently Aggarwal and co-workers25b 41

reported an efficient

allylboration method using α-substituted enantioenriched allylboronates (see

also Scheme 8) The method is highly diastereo- and enantioselective In

addition the procedure is suitable for the synthesis of homoallylic alcohols

with two adjacent quaternary stereocenters (Scheme 15)

Scheme 15 Asymmetric allylation of ketone by α-substituted chiral allylboronate

25b

An alternative approach for the asymmetric allylboration of carbonyl

compounds involves the application of chiral catalysts Both Lewis and

Broslashnsted acids have been used for the asymmetric allylboration reactions

The first catalytic enantioselective allylboration reaction was reported by

Miyaura and co-workers (Scheme 16)33c

This reaction proceeded with a

high regio- and diastereoselectivity but the enantioselectivity was relatively

low

Scheme 16 Catalytic asymmetric allylboration of aldehyde

33c

Hall and co-workers42

reported a Sn-catalyzed asymmetric allylboration

reaction using allyl-Bpin as the allyl source A chiral diol was used as a lig-

and in this process which was supposed to coordinate to SnCl4 (Scheme 17)

8

Scheme 17 Tin-catalyzed asymmetric allylboration of aldehyde

42a

Asymmetric allylation of ketones was reported using chiral allylboronate

derived from BINOL compounds Chong and co-workers described the al-

lylation of ketones using 33-(CF3)2-BINOL boronate 3a (Scheme 18)43

The

reaction gave homoallylic alcohol product with a high level of enantioselec-

tivity

Scheme 18 Asymmetric allylation of ketone using BINOL-boronate

43

Catalytic methods have also been described to control both diastereo- and

enantioselectivity in the allylboration of ketones44

The first catalytic

enantioselective allylboration of ketones was developed by Shibasaki and

co-workers45

Broslashnsted acid such as BINOL derivatives44 46

was found to be

very efficient in the asymmetric allylboration reactions Schaus and

co-workers44

reported a method for asymmetric allylation of ketones using

isopropoxyboronate and catalytic amounts of Br2-BINOL 4a (Scheme 19)

Scheme 19 Catalytic asymmetric allylboration of ketone using Br2-BINOL

44a

These authors proposed a Zimmerman-Traxler type transition state to

rationalize the enantioselectivity in this reaction It has been also pointed out

that the substituent in BINOL (eg Br or CF3) has an important role for the

enantioselectivity of these reactions

Catalytic synthesis of homoallylic alcohols containing adjacent quater-

nary stereocenters has been a great challenge in synthetic organic chemistry

A new synthetic method for such reaction is presented in Section 52

9

133 Stereoselective allylation of imines

Homoallylic amine motifs occur in many natural products and biological-

ly relevant compounds47

One of the most common strategies for homoallylic

amine synthesis is the addition of allyl-metal reagents to imines48

The use of

allylboronate compounds for these reactions has emerged as an important

synthetic approach47

Allylboronates have a low toxicity high functional

group tolerance and the allylation of imines occurs with a high level of

selectivity

Stereoselective allylation of aldimines can be performed by

allylboronates in the presence of Lewis acid catalysts Batey and

co-workers49

reported the allylboration of N-toluenesulfonylimines using

crotyltrifluroboronate and BF3OEt2 (Scheme 20) The allylation was

proposed to proceed via the allyl-BF2 species which is generated from

allyl-BF3K

Scheme 20 Stereoselective allylation of imine by allyltrifluoroborate

49

Kobayashi and co-workers50

reported a three-component diastereoselec-

tive allylation reaction to synthesize homoallylic primary amines (Scheme

21) In addition several useful methods for asymmetric allylboration of

imines25b 51

using allylboronates can also be found in literature

Scheme 21 Synthesis of homoallylic amine using multicomponent method

50

Allylboration of acylhydrazones have also proven to be a very useful

reaction for the synthesis of homoallylic amine derivatives However the

allylation of acylhydrazones by allylboronates requires the application of

metal catalysts52

An indium-catalyzed reaction for the allylation of N-

acylhydrazone was reported by Kobayashi and co-workers (Scheme 22)52a

It

has been proposed that indium undergoes a transmetallation with allyl-Bpin

to form an active allyl-indium species which then added to the hydrazone

10

Scheme 22 Indium-catalyzed allylation of acylhydrazone

52a

We have developed a stereoselective method for allylation of imines and

acylhydrazones using allylboronic acids These results are summarized in

Chapter 6

11

2 Pd-catalyzed stereoselective allylic CminusH

trifluoroacetoxylation (Paper I)

As mentioned in the introduction transition metal-catalyzed CminusH bond activation methods have attracted increasing interest in organic synthesis

53

Using these methods multistep synthesis for prefunctionalization of the or-ganic substrates is not necessary In addition the waste production of the reaction can be reduced as the new functional group can be installed by re-placement of hydrogen

54 Palladium-catalyzed allylic CminusH bond activation is

one of the oldest and most versatile CminusH functionalization method (Section 11)

55 In this reaction (as in CminusH activation based processes in general) the

greatest challenge is the control of the regio- and stereoselectivity of the process

Stereodefined allylic acetates are very important precursors for regio- and stereoselective palladium-catalyzed allylic substitution reactions

56 Although

many regioselective allylic CminusH functionalization methods have been re-ported there are few reports on stereoselective allylic CminusH acetoxylation

7a

Most of these studies are intramolecular CminusH acyloxylation reactions For example a stereoselective allylic CminusH acetoxylation method has been re-ported by White and co-workers (Scheme 23) Intramolecular selectivity control allowed macrocyclization

57 and straightforward synthesis of anti-14-

dioxan-2-ones58

from simple olefins using Pd(II)sulfoxide catalysis Baumlck-vall and co-workers

59 have also developed several methods for the synthesis

of allylacetoxy compounds based on palladium-catalyzed intramolecular oxidative carbocyclization

Scheme 23 Stereoselective intramolecular CminusH oxidation reported by White and

co-workers58

12

21 Development of selective intermolecular allylic CminusH trifluoroacetoxylation

As our group previously developed a useful allylic CminusH acetoxylation

method based on using PhI(OAc)2 (2a) (see Section 11) as oxidant and ace-

tate source we envisioned that PhI(OCOCF3)2 (2b) can also be used in this

type of reaction to introduce a trifluoroacetate group at the allylic position of

alkenes Allylic trifluoroacetates are more reactive than allylic acetates in

transition metal-catalyzed substitutions60

and therefore an easy access to

these compounds is desirable As far as we know selective allylic CminusH tri-

fluoroacetoxylation has not been reported in the literature

In the early stage of development and optimization we employed car-

boxylated alkene 6a as our model substrate as it gave a high yield and ex-

hibited high selectivity in the Pd-catalyzed CminusH acetoxylation with 2a11b

However PhI(OCOCF3)2 (2b) is most likely a stronger oxidant than

PhI(OAc)2 (2a) and therefore we could not use oxidation sensitive solvents

such as THF or DMSO In addition the conjugated acid of the trifluoroace-

tate ion (the nucleophile) is a strong acid and therefore trifluoroacetic acid

could not be used as the solvent either After short optimization we have

found that dimethyl carbonate (DMC) is an excellent solvent for all reaction

components and it is not oxidized by PIFA We have found that the isolated

yields are higher when LiOCOCF3 is used as additive Under these condi-

tions the reaction could be performed with various functionalized alkenes

(Table 1)

13

Table 1 Pd-catalyzed allylic CminusH trifluoroacetoxylation of acyclic olefinsa

Both Pd(OAc)2 (5b) and Pd(OCOCF3)2 (5c) were equally efficient as cat-

alyst in the reaction So we decided to use 5b in the present synthetic method

as it is less expensive than 5c Not only terminal (6a) but internal alkenes

6b-c could also be used for trifluoroacetoxylation with high selectivity Oth-

er alkenes with electron withdrawing substituents such as 6d-e could also be

smoothly trifluoroacetoxylated Substrates without electron-withdrawing

groups gave intractable mixtures of trifluoroacetoxylated products For com-

pounds with long alkyl chain oxidation of the double bond occurred while in

the case of electron donating substituents mainly oxidation of the double

bond occurred together with other processes

14

Table 2 Stereoselective allylic CminusH trifluoroacetoxylation of cyclic alkenesa

Not only acyclic alkenes but cyclic alkenes could also be employed for

the trifluoroacetoxylation reaction Monosubstituted cyclic alkenes reacted

with a remarkably high selectivity (Table 2) The reaction conditions were

very similar to the trifluoroacetoxylation of acyclic substrates (Table 1) but

in order to get this high stereoselectivity the reactions had to be conducted

at 0 degC This is below the freezing point of DMC therefore the reaction me-

dium was diluted with DCM to avoid freezing of the reaction mixture The

yields with LiOCOCF3 were as high as in its absence therefore we did not

use this additive in the trifluoroacetoxylation of cyclic substrates

Considering the number of possible regio- and stereoisomers a mixture

of six allylic trifluoroacetate products could be expected Yet in most cases

we obtained a single diastereomer with very high regioselectivity (Table 2

entries 1-2 and 4-5) The major regioisomer in all cases was the 14-

substituted product (7f-j) with anti diastereoselectivity and the minor prod-

uct is the regioisomer of the same diastereomer The stereochemistry of the

major isomers was assigned based on NOE experiments

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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65

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xi

Abbreviations

Abbreviations are used in agreement with standards of the subject1 Addi-

tional non-standard or unconventional abbreviations that appear in this thesis

are listed below

B2pin2 bis(pinacolato)diboron

BINOL 11-bi-2-naphthol

Bpin pinacolato boron

BQ 14-benzoquinone

dba dibenzylideneacetone

DFT density functional theory

DMC dimethyl carbonate

dr diastereomeric ratio

er enantiomeric ratio

LA Lewis acid

L ligand (neutral)

L chiral ligand

MS molecular sieves

NOE nuclear Overhauser effect

PIFA phenyliodine bis(trifluoroacetate)

PIDA phenyliodonium diacetate

TFA trifluoroacetate

TS transition state

rt room temperature

X ligand (charged)

1

1 Introduction

The development of highly selective transformations is of fundamental

importance in modern organic chemistry Transition metal-catalysis is one of

the useful synthetic approaches to achieve this goal2 The allylation reaction

using allylboron reagents and other allyl sources is also an important ap-

proach to develop selective syntheses3

11 Palladium-catalyzed allylic CminusH acetoxylation

Transition metal-catalyzed substitution of allylic acetates and their ana-

logs is one of the most utilized and studied reactions4 An important method

to synthesize allylic acetates is Pd-catalyzed allylic CminusH functionalization5

Pioneering works by McMurry and Kocovsky6 and Aringkermark

7 have shown

that Pd(II)-catalyzed allylic acetoxylation of cyclic and acyclic olefins can

be achieved in the presence of acetic acid and benzoquinone (BQ) as oxidant

(Scheme 1) Mechanistic investigations by Baumlckvall8 and co-workers

indicated that a (π-allyl)palladium(II) intermediates are involved in the

process and that BQ serves as both oxidant and activator ligand in the

CminusOAc bond formation process

Scheme 1 Pd-catalyzed allylic CminusH acetoxylation reaction

7a

Recently the White9 and the Stahl

10 group independently reported new

methods for CminusH acetoxylation reactions using palladium catalysis The

latter group used O2 as an oxidant instead of BQ According to the mechanis-

tic studies by these authors the CminusH acetoxylation process take place via

Pd0 and Pd

II catalytic intermediates

Hypervalent iodine reagents were also employed as the principal compo-

nent in the allylic CminusH oxidation reactions5 11

For example Szaboacute and

co-workers11b

have reported the allylic CminusH acyloxylation reaction with

PhI(OAc)2 (2a) as the oxidant and source of OAc (Scheme 2) The use of a

2

palladium catalysts and hypervalent iodine reagents allowed an easy access

to allylic acetoxy and benzoyloxy compounds Based on the mechanistic

studies a PdIIPd

IV catalytic cycle was proposed when PhI(OAc)2 was used

as the oxidant

Scheme 2 Pd-catalyzed CminusH acetoxylation reaction reported by Szaboacute and co-

workers11b

In spite of the wide application of allylic CminusH acyloxylation reactions in

organic synthesis the stereoselective transformations of substituted cyclic

alkenes are limited Particularly the intermolecular diastereoselective CminusH

acyloxylation is still a challenge A new synthetic process for such a reaction

is presented in Chapter 2

12 Synthesis of allylboronates

Allylboronates are efficient reagents for regio- and stereoselective allyla-

tion of carbonyl compounds and some related functionalities3 12

Due to the

importance of allylboronates in synthetic organic chemistry there has been a

large interest in the development of new methods for the synthesis of these

reagents The classical synthetic procedures involve application of allyl-

Grignard and allyl-Li reagents13

However these methods have a limited

synthetic scope because of problems with the regioselective formation of the

allylboronates Palladium-catalyzed methods based on the substitution of allylic alcohol

derivatives have proven to be a versatile and relatively simple method to

obtain allylboronates The first process was reported by Miyaura and

co-workers14

(Scheme 3) In this process B2pin2 was used as the boron

source Although the regioselectivity of the reaction is excellent a drawback

of this process is the formation of varying amounts of homocoupling prod-

ucts

Scheme 3 Pd-catalyzed borylation of allylacetates

14

The Szaboacute group15

has expanded the substrate scope to include allylic

alcohols instead of allylic acetates (Scheme 4) It was also shown that

3

certain Pd(II) pincer complexes are more efficient than Pd(dba)2 In depth

mechanistic studies revealed that catalytic amounts of Lewis or Broslashnsted

acids are required in the reaction to activate the allylic alcohols for Pd-

catalyzed substitution16

The reaction is substantially accelerated in the pres-

ence of MeOH or other protic co-solvents

Scheme 4 Pd-catalyzed borylation of allylic alcohols

15c 15d

The Szaboacute group also developed palladium-catalyzed allylic C-H boryla-

tion methods17

These processes allowed for the synthesis of allylboronates

from readily available alkenes under oxidative conditions using BQ (1) or

the hypervalent iodonium salt

Ito Sawamura and their co-workers reported the regio- and stereoselec-

tive synthesis of allylboronates by Cu-catalyzed substitution of allyl

carbonates18

This method can also be extended to asymmetric catalysis for

the synthesis of enantioenriched allylboronates (Scheme 5)19

Scheme 5 Cu-catalyzed asymmetric borylation of allylcarbonates

19

Enantioselective synthesis of α-substituted allylboronates has been

reported by Hall and co-workers (Scheme 6)20

This method is based on

copper-catalyzed substitution of allylhalide substrates The chiral

allylboronates generated in this reaction were used for further transformation

without isolation

Scheme 6 Cu-catalyzed borylation reported by Hall and co-workers

20

Related Cu-catalyzed asymmetric synthesis of allylboronates have also

been independently reported by the groups of Hoveyda21

and McQuade22

Nickel-catalyzed stereospecific borylation of allylic acetates was developed

by Morken and co-workers23

The reaction is highly selective for the termi-

4

nal allylboronates (Scheme 7) The Morken group also developed palladi-

um-catalyzed enantioselective borylation methods for the synthesis of al-

lylboronates24

Scheme 7 Ni-catalyzed selective borylation of allylic acetates

23

Very recently Aggarwal and co-workers have reported a new method for

the preparation of enantioenriched allylboronates25

This so called ldquolithia-

tion-borylation methodrdquo involves homologation of vinyl boronates using

alkyl carbamates and butyllithium (BuLi) in the presence of (+)-sparteine

(Scheme 8)

Scheme 8 Synthesis of allylboronates by lithiation-borylation method

25b

As shown above synthesis of allylboron reagents has attracted large in-

terest in modern organic chemistry As a contribution to this field we devel-

oped a new method for the synthesis and isolation of allylboronic acids

which is presented in Chapter 3

13 Application of allylboronates in synthesis

Allylboronate reagents have been extensively used to synthesize numerous precursors for natural products and bioactive molecules

26

Addition of allylboronates to carbonyl and imine electrophiles is a well studied and documented reactions in synthetic organic chemistry

131 Stereoselective allylation of carbonyl compounds

Allylboration reactions of aldehydes have been widely applied for the ste-

reoselective synthesis of homoallylic alcohols3 After the discovery by Bub-

nov27

the reaction was further developed by Hoffmann28

Brown29

Roush30

and others Hoffmann and Brown carried out in depth mechanistic studies

which also explained the stereochemistry of the reaction Hoffman postulat-

ed that the reaction between allylboronates and aldehydes proceeds via a six-

5

membered cyclic TS similar to the Zimmerman-Traxler31

model (Scheme

9)28a 32

The high diastereoselectivity of the allylboration reaction is attributed to

an internal Lewis acid activation of the carbonyl functionality by the empty

p-orbital of boron

Scheme 9 Zimmerman-Traxler model to describe stereochemistry of allylboration

reaction

The addition of Lewis or Broslashnsted acids may accelerate the allylboration

of carbonyl compounds33

Hall and co-workers proposed that Lewis acids

coordinate to the lone pair of the boronate oxygen which renders the boron

atom more electron deficient (Scheme 10)33b 34

This mechanism for LA

and Broslashnsted acid activation was also confirmed by the DFT studies of

Houk and co-workers35

Scheme 10 Possible modes of Lewis acid activation for the allylboration

Allylboronates can also react with ketones yielding tertiary homoallylic

alcohols However the addition of allylboronates to ketones is much slower

than similar reactions with aldehydes Thus the selective allylation of

ketones with allylboronates often requires the use of catalysts36

In addition

most of the present methods for allylboration of ketones are limited to the

use of unsubstituted (parent) allylboronates or crotylboronates

132 Enantioselective allylation of carbonyl compounds

There are basically two main approaches for the asymmetric allylboration

of carbonyl compounds The first approach is the application of enantioen-

riched allylboronates performing chirality transfer and the second one is

6

asymmetric induction by using chiral catalyst One of the first asymmetric

allylboration reactions was reported by Roush and co-workers 13b 37

These

authors employed chiral auxiliaries attached to the boron atom (Scheme 11)

Diisopropyl tartrate (DIPT) proved to be a very efficient chiral auxiliary to

induce enantioselectivity

Scheme 11 Asymmetric allylation of aldehydes using chiral allylboronate

13b

A similar approach was reported by Soderquist and co-workers38

for the

asymmetric allylboration of aldehyde and ketones A bicyclic chiral auxilia-

ry on the boron atom was employed for highly diastereo- and enantioselec-

tive allylboration (Scheme 12)

Scheme 12 Diastereo-and enantioselective allylboration by chiral allylborane

38a

Enantiomerically pure TADDOL based allylboronates were developed by

Pietruszka and co-workers39

These reagents were used for chirality transfer

in allylboration of aldehydes (Scheme 13) The chiral auxiliary can be

recovered after the allylation by reduction with LiAlH4

Scheme 13 Asymmetric allylation of aldehyde using enantiopure allylboronate

39

Metal-catalyzed asymmetric synthesis of heterocyclic allylboronates was

described by Hall and co-workers40

These allylboronates were used in situ

for allylboration of aldehydes The key-step in synthesis of mefloquine was

performed using this method (Scheme 14)

7

Scheme 14 Asymmetric allylboration by cyclic allylboronates

40

Very recently Aggarwal and co-workers25b 41

reported an efficient

allylboration method using α-substituted enantioenriched allylboronates (see

also Scheme 8) The method is highly diastereo- and enantioselective In

addition the procedure is suitable for the synthesis of homoallylic alcohols

with two adjacent quaternary stereocenters (Scheme 15)

Scheme 15 Asymmetric allylation of ketone by α-substituted chiral allylboronate

25b

An alternative approach for the asymmetric allylboration of carbonyl

compounds involves the application of chiral catalysts Both Lewis and

Broslashnsted acids have been used for the asymmetric allylboration reactions

The first catalytic enantioselective allylboration reaction was reported by

Miyaura and co-workers (Scheme 16)33c

This reaction proceeded with a

high regio- and diastereoselectivity but the enantioselectivity was relatively

low

Scheme 16 Catalytic asymmetric allylboration of aldehyde

33c

Hall and co-workers42

reported a Sn-catalyzed asymmetric allylboration

reaction using allyl-Bpin as the allyl source A chiral diol was used as a lig-

and in this process which was supposed to coordinate to SnCl4 (Scheme 17)

8

Scheme 17 Tin-catalyzed asymmetric allylboration of aldehyde

42a

Asymmetric allylation of ketones was reported using chiral allylboronate

derived from BINOL compounds Chong and co-workers described the al-

lylation of ketones using 33-(CF3)2-BINOL boronate 3a (Scheme 18)43

The

reaction gave homoallylic alcohol product with a high level of enantioselec-

tivity

Scheme 18 Asymmetric allylation of ketone using BINOL-boronate

43

Catalytic methods have also been described to control both diastereo- and

enantioselectivity in the allylboration of ketones44

The first catalytic

enantioselective allylboration of ketones was developed by Shibasaki and

co-workers45

Broslashnsted acid such as BINOL derivatives44 46

was found to be

very efficient in the asymmetric allylboration reactions Schaus and

co-workers44

reported a method for asymmetric allylation of ketones using

isopropoxyboronate and catalytic amounts of Br2-BINOL 4a (Scheme 19)

Scheme 19 Catalytic asymmetric allylboration of ketone using Br2-BINOL

44a

These authors proposed a Zimmerman-Traxler type transition state to

rationalize the enantioselectivity in this reaction It has been also pointed out

that the substituent in BINOL (eg Br or CF3) has an important role for the

enantioselectivity of these reactions

Catalytic synthesis of homoallylic alcohols containing adjacent quater-

nary stereocenters has been a great challenge in synthetic organic chemistry

A new synthetic method for such reaction is presented in Section 52

9

133 Stereoselective allylation of imines

Homoallylic amine motifs occur in many natural products and biological-

ly relevant compounds47

One of the most common strategies for homoallylic

amine synthesis is the addition of allyl-metal reagents to imines48

The use of

allylboronate compounds for these reactions has emerged as an important

synthetic approach47

Allylboronates have a low toxicity high functional

group tolerance and the allylation of imines occurs with a high level of

selectivity

Stereoselective allylation of aldimines can be performed by

allylboronates in the presence of Lewis acid catalysts Batey and

co-workers49

reported the allylboration of N-toluenesulfonylimines using

crotyltrifluroboronate and BF3OEt2 (Scheme 20) The allylation was

proposed to proceed via the allyl-BF2 species which is generated from

allyl-BF3K

Scheme 20 Stereoselective allylation of imine by allyltrifluoroborate

49

Kobayashi and co-workers50

reported a three-component diastereoselec-

tive allylation reaction to synthesize homoallylic primary amines (Scheme

21) In addition several useful methods for asymmetric allylboration of

imines25b 51

using allylboronates can also be found in literature

Scheme 21 Synthesis of homoallylic amine using multicomponent method

50

Allylboration of acylhydrazones have also proven to be a very useful

reaction for the synthesis of homoallylic amine derivatives However the

allylation of acylhydrazones by allylboronates requires the application of

metal catalysts52

An indium-catalyzed reaction for the allylation of N-

acylhydrazone was reported by Kobayashi and co-workers (Scheme 22)52a

It

has been proposed that indium undergoes a transmetallation with allyl-Bpin

to form an active allyl-indium species which then added to the hydrazone

10

Scheme 22 Indium-catalyzed allylation of acylhydrazone

52a

We have developed a stereoselective method for allylation of imines and

acylhydrazones using allylboronic acids These results are summarized in

Chapter 6

11

2 Pd-catalyzed stereoselective allylic CminusH

trifluoroacetoxylation (Paper I)

As mentioned in the introduction transition metal-catalyzed CminusH bond activation methods have attracted increasing interest in organic synthesis

53

Using these methods multistep synthesis for prefunctionalization of the or-ganic substrates is not necessary In addition the waste production of the reaction can be reduced as the new functional group can be installed by re-placement of hydrogen

54 Palladium-catalyzed allylic CminusH bond activation is

one of the oldest and most versatile CminusH functionalization method (Section 11)

55 In this reaction (as in CminusH activation based processes in general) the

greatest challenge is the control of the regio- and stereoselectivity of the process

Stereodefined allylic acetates are very important precursors for regio- and stereoselective palladium-catalyzed allylic substitution reactions

56 Although

many regioselective allylic CminusH functionalization methods have been re-ported there are few reports on stereoselective allylic CminusH acetoxylation

7a

Most of these studies are intramolecular CminusH acyloxylation reactions For example a stereoselective allylic CminusH acetoxylation method has been re-ported by White and co-workers (Scheme 23) Intramolecular selectivity control allowed macrocyclization

57 and straightforward synthesis of anti-14-

dioxan-2-ones58

from simple olefins using Pd(II)sulfoxide catalysis Baumlck-vall and co-workers

59 have also developed several methods for the synthesis

of allylacetoxy compounds based on palladium-catalyzed intramolecular oxidative carbocyclization

Scheme 23 Stereoselective intramolecular CminusH oxidation reported by White and

co-workers58

12

21 Development of selective intermolecular allylic CminusH trifluoroacetoxylation

As our group previously developed a useful allylic CminusH acetoxylation

method based on using PhI(OAc)2 (2a) (see Section 11) as oxidant and ace-

tate source we envisioned that PhI(OCOCF3)2 (2b) can also be used in this

type of reaction to introduce a trifluoroacetate group at the allylic position of

alkenes Allylic trifluoroacetates are more reactive than allylic acetates in

transition metal-catalyzed substitutions60

and therefore an easy access to

these compounds is desirable As far as we know selective allylic CminusH tri-

fluoroacetoxylation has not been reported in the literature

In the early stage of development and optimization we employed car-

boxylated alkene 6a as our model substrate as it gave a high yield and ex-

hibited high selectivity in the Pd-catalyzed CminusH acetoxylation with 2a11b

However PhI(OCOCF3)2 (2b) is most likely a stronger oxidant than

PhI(OAc)2 (2a) and therefore we could not use oxidation sensitive solvents

such as THF or DMSO In addition the conjugated acid of the trifluoroace-

tate ion (the nucleophile) is a strong acid and therefore trifluoroacetic acid

could not be used as the solvent either After short optimization we have

found that dimethyl carbonate (DMC) is an excellent solvent for all reaction

components and it is not oxidized by PIFA We have found that the isolated

yields are higher when LiOCOCF3 is used as additive Under these condi-

tions the reaction could be performed with various functionalized alkenes

(Table 1)

13

Table 1 Pd-catalyzed allylic CminusH trifluoroacetoxylation of acyclic olefinsa

Both Pd(OAc)2 (5b) and Pd(OCOCF3)2 (5c) were equally efficient as cat-

alyst in the reaction So we decided to use 5b in the present synthetic method

as it is less expensive than 5c Not only terminal (6a) but internal alkenes

6b-c could also be used for trifluoroacetoxylation with high selectivity Oth-

er alkenes with electron withdrawing substituents such as 6d-e could also be

smoothly trifluoroacetoxylated Substrates without electron-withdrawing

groups gave intractable mixtures of trifluoroacetoxylated products For com-

pounds with long alkyl chain oxidation of the double bond occurred while in

the case of electron donating substituents mainly oxidation of the double

bond occurred together with other processes

14

Table 2 Stereoselective allylic CminusH trifluoroacetoxylation of cyclic alkenesa

Not only acyclic alkenes but cyclic alkenes could also be employed for

the trifluoroacetoxylation reaction Monosubstituted cyclic alkenes reacted

with a remarkably high selectivity (Table 2) The reaction conditions were

very similar to the trifluoroacetoxylation of acyclic substrates (Table 1) but

in order to get this high stereoselectivity the reactions had to be conducted

at 0 degC This is below the freezing point of DMC therefore the reaction me-

dium was diluted with DCM to avoid freezing of the reaction mixture The

yields with LiOCOCF3 were as high as in its absence therefore we did not

use this additive in the trifluoroacetoxylation of cyclic substrates

Considering the number of possible regio- and stereoisomers a mixture

of six allylic trifluoroacetate products could be expected Yet in most cases

we obtained a single diastereomer with very high regioselectivity (Table 2

entries 1-2 and 4-5) The major regioisomer in all cases was the 14-

substituted product (7f-j) with anti diastereoselectivity and the minor prod-

uct is the regioisomer of the same diastereomer The stereochemistry of the

major isomers was assigned based on NOE experiments

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

1 The ACS Style Guide 3rd ed Oxford University Press New York 2006

2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

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18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

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10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

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62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

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37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

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40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

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7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

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the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

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64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

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65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

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94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

1

1 Introduction

The development of highly selective transformations is of fundamental

importance in modern organic chemistry Transition metal-catalysis is one of

the useful synthetic approaches to achieve this goal2 The allylation reaction

using allylboron reagents and other allyl sources is also an important ap-

proach to develop selective syntheses3

11 Palladium-catalyzed allylic CminusH acetoxylation

Transition metal-catalyzed substitution of allylic acetates and their ana-

logs is one of the most utilized and studied reactions4 An important method

to synthesize allylic acetates is Pd-catalyzed allylic CminusH functionalization5

Pioneering works by McMurry and Kocovsky6 and Aringkermark

7 have shown

that Pd(II)-catalyzed allylic acetoxylation of cyclic and acyclic olefins can

be achieved in the presence of acetic acid and benzoquinone (BQ) as oxidant

(Scheme 1) Mechanistic investigations by Baumlckvall8 and co-workers

indicated that a (π-allyl)palladium(II) intermediates are involved in the

process and that BQ serves as both oxidant and activator ligand in the

CminusOAc bond formation process

Scheme 1 Pd-catalyzed allylic CminusH acetoxylation reaction

7a

Recently the White9 and the Stahl

10 group independently reported new

methods for CminusH acetoxylation reactions using palladium catalysis The

latter group used O2 as an oxidant instead of BQ According to the mechanis-

tic studies by these authors the CminusH acetoxylation process take place via

Pd0 and Pd

II catalytic intermediates

Hypervalent iodine reagents were also employed as the principal compo-

nent in the allylic CminusH oxidation reactions5 11

For example Szaboacute and

co-workers11b

have reported the allylic CminusH acyloxylation reaction with

PhI(OAc)2 (2a) as the oxidant and source of OAc (Scheme 2) The use of a

2

palladium catalysts and hypervalent iodine reagents allowed an easy access

to allylic acetoxy and benzoyloxy compounds Based on the mechanistic

studies a PdIIPd

IV catalytic cycle was proposed when PhI(OAc)2 was used

as the oxidant

Scheme 2 Pd-catalyzed CminusH acetoxylation reaction reported by Szaboacute and co-

workers11b

In spite of the wide application of allylic CminusH acyloxylation reactions in

organic synthesis the stereoselective transformations of substituted cyclic

alkenes are limited Particularly the intermolecular diastereoselective CminusH

acyloxylation is still a challenge A new synthetic process for such a reaction

is presented in Chapter 2

12 Synthesis of allylboronates

Allylboronates are efficient reagents for regio- and stereoselective allyla-

tion of carbonyl compounds and some related functionalities3 12

Due to the

importance of allylboronates in synthetic organic chemistry there has been a

large interest in the development of new methods for the synthesis of these

reagents The classical synthetic procedures involve application of allyl-

Grignard and allyl-Li reagents13

However these methods have a limited

synthetic scope because of problems with the regioselective formation of the

allylboronates Palladium-catalyzed methods based on the substitution of allylic alcohol

derivatives have proven to be a versatile and relatively simple method to

obtain allylboronates The first process was reported by Miyaura and

co-workers14

(Scheme 3) In this process B2pin2 was used as the boron

source Although the regioselectivity of the reaction is excellent a drawback

of this process is the formation of varying amounts of homocoupling prod-

ucts

Scheme 3 Pd-catalyzed borylation of allylacetates

14

The Szaboacute group15

has expanded the substrate scope to include allylic

alcohols instead of allylic acetates (Scheme 4) It was also shown that

3

certain Pd(II) pincer complexes are more efficient than Pd(dba)2 In depth

mechanistic studies revealed that catalytic amounts of Lewis or Broslashnsted

acids are required in the reaction to activate the allylic alcohols for Pd-

catalyzed substitution16

The reaction is substantially accelerated in the pres-

ence of MeOH or other protic co-solvents

Scheme 4 Pd-catalyzed borylation of allylic alcohols

15c 15d

The Szaboacute group also developed palladium-catalyzed allylic C-H boryla-

tion methods17

These processes allowed for the synthesis of allylboronates

from readily available alkenes under oxidative conditions using BQ (1) or

the hypervalent iodonium salt

Ito Sawamura and their co-workers reported the regio- and stereoselec-

tive synthesis of allylboronates by Cu-catalyzed substitution of allyl

carbonates18

This method can also be extended to asymmetric catalysis for

the synthesis of enantioenriched allylboronates (Scheme 5)19

Scheme 5 Cu-catalyzed asymmetric borylation of allylcarbonates

19

Enantioselective synthesis of α-substituted allylboronates has been

reported by Hall and co-workers (Scheme 6)20

This method is based on

copper-catalyzed substitution of allylhalide substrates The chiral

allylboronates generated in this reaction were used for further transformation

without isolation

Scheme 6 Cu-catalyzed borylation reported by Hall and co-workers

20

Related Cu-catalyzed asymmetric synthesis of allylboronates have also

been independently reported by the groups of Hoveyda21

and McQuade22

Nickel-catalyzed stereospecific borylation of allylic acetates was developed

by Morken and co-workers23

The reaction is highly selective for the termi-

4

nal allylboronates (Scheme 7) The Morken group also developed palladi-

um-catalyzed enantioselective borylation methods for the synthesis of al-

lylboronates24

Scheme 7 Ni-catalyzed selective borylation of allylic acetates

23

Very recently Aggarwal and co-workers have reported a new method for

the preparation of enantioenriched allylboronates25

This so called ldquolithia-

tion-borylation methodrdquo involves homologation of vinyl boronates using

alkyl carbamates and butyllithium (BuLi) in the presence of (+)-sparteine

(Scheme 8)

Scheme 8 Synthesis of allylboronates by lithiation-borylation method

25b

As shown above synthesis of allylboron reagents has attracted large in-

terest in modern organic chemistry As a contribution to this field we devel-

oped a new method for the synthesis and isolation of allylboronic acids

which is presented in Chapter 3

13 Application of allylboronates in synthesis

Allylboronate reagents have been extensively used to synthesize numerous precursors for natural products and bioactive molecules

26

Addition of allylboronates to carbonyl and imine electrophiles is a well studied and documented reactions in synthetic organic chemistry

131 Stereoselective allylation of carbonyl compounds

Allylboration reactions of aldehydes have been widely applied for the ste-

reoselective synthesis of homoallylic alcohols3 After the discovery by Bub-

nov27

the reaction was further developed by Hoffmann28

Brown29

Roush30

and others Hoffmann and Brown carried out in depth mechanistic studies

which also explained the stereochemistry of the reaction Hoffman postulat-

ed that the reaction between allylboronates and aldehydes proceeds via a six-

5

membered cyclic TS similar to the Zimmerman-Traxler31

model (Scheme

9)28a 32

The high diastereoselectivity of the allylboration reaction is attributed to

an internal Lewis acid activation of the carbonyl functionality by the empty

p-orbital of boron

Scheme 9 Zimmerman-Traxler model to describe stereochemistry of allylboration

reaction

The addition of Lewis or Broslashnsted acids may accelerate the allylboration

of carbonyl compounds33

Hall and co-workers proposed that Lewis acids

coordinate to the lone pair of the boronate oxygen which renders the boron

atom more electron deficient (Scheme 10)33b 34

This mechanism for LA

and Broslashnsted acid activation was also confirmed by the DFT studies of

Houk and co-workers35

Scheme 10 Possible modes of Lewis acid activation for the allylboration

Allylboronates can also react with ketones yielding tertiary homoallylic

alcohols However the addition of allylboronates to ketones is much slower

than similar reactions with aldehydes Thus the selective allylation of

ketones with allylboronates often requires the use of catalysts36

In addition

most of the present methods for allylboration of ketones are limited to the

use of unsubstituted (parent) allylboronates or crotylboronates

132 Enantioselective allylation of carbonyl compounds

There are basically two main approaches for the asymmetric allylboration

of carbonyl compounds The first approach is the application of enantioen-

riched allylboronates performing chirality transfer and the second one is

6

asymmetric induction by using chiral catalyst One of the first asymmetric

allylboration reactions was reported by Roush and co-workers 13b 37

These

authors employed chiral auxiliaries attached to the boron atom (Scheme 11)

Diisopropyl tartrate (DIPT) proved to be a very efficient chiral auxiliary to

induce enantioselectivity

Scheme 11 Asymmetric allylation of aldehydes using chiral allylboronate

13b

A similar approach was reported by Soderquist and co-workers38

for the

asymmetric allylboration of aldehyde and ketones A bicyclic chiral auxilia-

ry on the boron atom was employed for highly diastereo- and enantioselec-

tive allylboration (Scheme 12)

Scheme 12 Diastereo-and enantioselective allylboration by chiral allylborane

38a

Enantiomerically pure TADDOL based allylboronates were developed by

Pietruszka and co-workers39

These reagents were used for chirality transfer

in allylboration of aldehydes (Scheme 13) The chiral auxiliary can be

recovered after the allylation by reduction with LiAlH4

Scheme 13 Asymmetric allylation of aldehyde using enantiopure allylboronate

39

Metal-catalyzed asymmetric synthesis of heterocyclic allylboronates was

described by Hall and co-workers40

These allylboronates were used in situ

for allylboration of aldehydes The key-step in synthesis of mefloquine was

performed using this method (Scheme 14)

7

Scheme 14 Asymmetric allylboration by cyclic allylboronates

40

Very recently Aggarwal and co-workers25b 41

reported an efficient

allylboration method using α-substituted enantioenriched allylboronates (see

also Scheme 8) The method is highly diastereo- and enantioselective In

addition the procedure is suitable for the synthesis of homoallylic alcohols

with two adjacent quaternary stereocenters (Scheme 15)

Scheme 15 Asymmetric allylation of ketone by α-substituted chiral allylboronate

25b

An alternative approach for the asymmetric allylboration of carbonyl

compounds involves the application of chiral catalysts Both Lewis and

Broslashnsted acids have been used for the asymmetric allylboration reactions

The first catalytic enantioselective allylboration reaction was reported by

Miyaura and co-workers (Scheme 16)33c

This reaction proceeded with a

high regio- and diastereoselectivity but the enantioselectivity was relatively

low

Scheme 16 Catalytic asymmetric allylboration of aldehyde

33c

Hall and co-workers42

reported a Sn-catalyzed asymmetric allylboration

reaction using allyl-Bpin as the allyl source A chiral diol was used as a lig-

and in this process which was supposed to coordinate to SnCl4 (Scheme 17)

8

Scheme 17 Tin-catalyzed asymmetric allylboration of aldehyde

42a

Asymmetric allylation of ketones was reported using chiral allylboronate

derived from BINOL compounds Chong and co-workers described the al-

lylation of ketones using 33-(CF3)2-BINOL boronate 3a (Scheme 18)43

The

reaction gave homoallylic alcohol product with a high level of enantioselec-

tivity

Scheme 18 Asymmetric allylation of ketone using BINOL-boronate

43

Catalytic methods have also been described to control both diastereo- and

enantioselectivity in the allylboration of ketones44

The first catalytic

enantioselective allylboration of ketones was developed by Shibasaki and

co-workers45

Broslashnsted acid such as BINOL derivatives44 46

was found to be

very efficient in the asymmetric allylboration reactions Schaus and

co-workers44

reported a method for asymmetric allylation of ketones using

isopropoxyboronate and catalytic amounts of Br2-BINOL 4a (Scheme 19)

Scheme 19 Catalytic asymmetric allylboration of ketone using Br2-BINOL

44a

These authors proposed a Zimmerman-Traxler type transition state to

rationalize the enantioselectivity in this reaction It has been also pointed out

that the substituent in BINOL (eg Br or CF3) has an important role for the

enantioselectivity of these reactions

Catalytic synthesis of homoallylic alcohols containing adjacent quater-

nary stereocenters has been a great challenge in synthetic organic chemistry

A new synthetic method for such reaction is presented in Section 52

9

133 Stereoselective allylation of imines

Homoallylic amine motifs occur in many natural products and biological-

ly relevant compounds47

One of the most common strategies for homoallylic

amine synthesis is the addition of allyl-metal reagents to imines48

The use of

allylboronate compounds for these reactions has emerged as an important

synthetic approach47

Allylboronates have a low toxicity high functional

group tolerance and the allylation of imines occurs with a high level of

selectivity

Stereoselective allylation of aldimines can be performed by

allylboronates in the presence of Lewis acid catalysts Batey and

co-workers49

reported the allylboration of N-toluenesulfonylimines using

crotyltrifluroboronate and BF3OEt2 (Scheme 20) The allylation was

proposed to proceed via the allyl-BF2 species which is generated from

allyl-BF3K

Scheme 20 Stereoselective allylation of imine by allyltrifluoroborate

49

Kobayashi and co-workers50

reported a three-component diastereoselec-

tive allylation reaction to synthesize homoallylic primary amines (Scheme

21) In addition several useful methods for asymmetric allylboration of

imines25b 51

using allylboronates can also be found in literature

Scheme 21 Synthesis of homoallylic amine using multicomponent method

50

Allylboration of acylhydrazones have also proven to be a very useful

reaction for the synthesis of homoallylic amine derivatives However the

allylation of acylhydrazones by allylboronates requires the application of

metal catalysts52

An indium-catalyzed reaction for the allylation of N-

acylhydrazone was reported by Kobayashi and co-workers (Scheme 22)52a

It

has been proposed that indium undergoes a transmetallation with allyl-Bpin

to form an active allyl-indium species which then added to the hydrazone

10

Scheme 22 Indium-catalyzed allylation of acylhydrazone

52a

We have developed a stereoselective method for allylation of imines and

acylhydrazones using allylboronic acids These results are summarized in

Chapter 6

11

2 Pd-catalyzed stereoselective allylic CminusH

trifluoroacetoxylation (Paper I)

As mentioned in the introduction transition metal-catalyzed CminusH bond activation methods have attracted increasing interest in organic synthesis

53

Using these methods multistep synthesis for prefunctionalization of the or-ganic substrates is not necessary In addition the waste production of the reaction can be reduced as the new functional group can be installed by re-placement of hydrogen

54 Palladium-catalyzed allylic CminusH bond activation is

one of the oldest and most versatile CminusH functionalization method (Section 11)

55 In this reaction (as in CminusH activation based processes in general) the

greatest challenge is the control of the regio- and stereoselectivity of the process

Stereodefined allylic acetates are very important precursors for regio- and stereoselective palladium-catalyzed allylic substitution reactions

56 Although

many regioselective allylic CminusH functionalization methods have been re-ported there are few reports on stereoselective allylic CminusH acetoxylation

7a

Most of these studies are intramolecular CminusH acyloxylation reactions For example a stereoselective allylic CminusH acetoxylation method has been re-ported by White and co-workers (Scheme 23) Intramolecular selectivity control allowed macrocyclization

57 and straightforward synthesis of anti-14-

dioxan-2-ones58

from simple olefins using Pd(II)sulfoxide catalysis Baumlck-vall and co-workers

59 have also developed several methods for the synthesis

of allylacetoxy compounds based on palladium-catalyzed intramolecular oxidative carbocyclization

Scheme 23 Stereoselective intramolecular CminusH oxidation reported by White and

co-workers58

12

21 Development of selective intermolecular allylic CminusH trifluoroacetoxylation

As our group previously developed a useful allylic CminusH acetoxylation

method based on using PhI(OAc)2 (2a) (see Section 11) as oxidant and ace-

tate source we envisioned that PhI(OCOCF3)2 (2b) can also be used in this

type of reaction to introduce a trifluoroacetate group at the allylic position of

alkenes Allylic trifluoroacetates are more reactive than allylic acetates in

transition metal-catalyzed substitutions60

and therefore an easy access to

these compounds is desirable As far as we know selective allylic CminusH tri-

fluoroacetoxylation has not been reported in the literature

In the early stage of development and optimization we employed car-

boxylated alkene 6a as our model substrate as it gave a high yield and ex-

hibited high selectivity in the Pd-catalyzed CminusH acetoxylation with 2a11b

However PhI(OCOCF3)2 (2b) is most likely a stronger oxidant than

PhI(OAc)2 (2a) and therefore we could not use oxidation sensitive solvents

such as THF or DMSO In addition the conjugated acid of the trifluoroace-

tate ion (the nucleophile) is a strong acid and therefore trifluoroacetic acid

could not be used as the solvent either After short optimization we have

found that dimethyl carbonate (DMC) is an excellent solvent for all reaction

components and it is not oxidized by PIFA We have found that the isolated

yields are higher when LiOCOCF3 is used as additive Under these condi-

tions the reaction could be performed with various functionalized alkenes

(Table 1)

13

Table 1 Pd-catalyzed allylic CminusH trifluoroacetoxylation of acyclic olefinsa

Both Pd(OAc)2 (5b) and Pd(OCOCF3)2 (5c) were equally efficient as cat-

alyst in the reaction So we decided to use 5b in the present synthetic method

as it is less expensive than 5c Not only terminal (6a) but internal alkenes

6b-c could also be used for trifluoroacetoxylation with high selectivity Oth-

er alkenes with electron withdrawing substituents such as 6d-e could also be

smoothly trifluoroacetoxylated Substrates without electron-withdrawing

groups gave intractable mixtures of trifluoroacetoxylated products For com-

pounds with long alkyl chain oxidation of the double bond occurred while in

the case of electron donating substituents mainly oxidation of the double

bond occurred together with other processes

14

Table 2 Stereoselective allylic CminusH trifluoroacetoxylation of cyclic alkenesa

Not only acyclic alkenes but cyclic alkenes could also be employed for

the trifluoroacetoxylation reaction Monosubstituted cyclic alkenes reacted

with a remarkably high selectivity (Table 2) The reaction conditions were

very similar to the trifluoroacetoxylation of acyclic substrates (Table 1) but

in order to get this high stereoselectivity the reactions had to be conducted

at 0 degC This is below the freezing point of DMC therefore the reaction me-

dium was diluted with DCM to avoid freezing of the reaction mixture The

yields with LiOCOCF3 were as high as in its absence therefore we did not

use this additive in the trifluoroacetoxylation of cyclic substrates

Considering the number of possible regio- and stereoisomers a mixture

of six allylic trifluoroacetate products could be expected Yet in most cases

we obtained a single diastereomer with very high regioselectivity (Table 2

entries 1-2 and 4-5) The major regioisomer in all cases was the 14-

substituted product (7f-j) with anti diastereoselectivity and the minor prod-

uct is the regioisomer of the same diastereomer The stereochemistry of the

major isomers was assigned based on NOE experiments

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

1 The ACS Style Guide 3rd ed Oxford University Press New York 2006

2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

2

palladium catalysts and hypervalent iodine reagents allowed an easy access

to allylic acetoxy and benzoyloxy compounds Based on the mechanistic

studies a PdIIPd

IV catalytic cycle was proposed when PhI(OAc)2 was used

as the oxidant

Scheme 2 Pd-catalyzed CminusH acetoxylation reaction reported by Szaboacute and co-

workers11b

In spite of the wide application of allylic CminusH acyloxylation reactions in

organic synthesis the stereoselective transformations of substituted cyclic

alkenes are limited Particularly the intermolecular diastereoselective CminusH

acyloxylation is still a challenge A new synthetic process for such a reaction

is presented in Chapter 2

12 Synthesis of allylboronates

Allylboronates are efficient reagents for regio- and stereoselective allyla-

tion of carbonyl compounds and some related functionalities3 12

Due to the

importance of allylboronates in synthetic organic chemistry there has been a

large interest in the development of new methods for the synthesis of these

reagents The classical synthetic procedures involve application of allyl-

Grignard and allyl-Li reagents13

However these methods have a limited

synthetic scope because of problems with the regioselective formation of the

allylboronates Palladium-catalyzed methods based on the substitution of allylic alcohol

derivatives have proven to be a versatile and relatively simple method to

obtain allylboronates The first process was reported by Miyaura and

co-workers14

(Scheme 3) In this process B2pin2 was used as the boron

source Although the regioselectivity of the reaction is excellent a drawback

of this process is the formation of varying amounts of homocoupling prod-

ucts

Scheme 3 Pd-catalyzed borylation of allylacetates

14

The Szaboacute group15

has expanded the substrate scope to include allylic

alcohols instead of allylic acetates (Scheme 4) It was also shown that

3

certain Pd(II) pincer complexes are more efficient than Pd(dba)2 In depth

mechanistic studies revealed that catalytic amounts of Lewis or Broslashnsted

acids are required in the reaction to activate the allylic alcohols for Pd-

catalyzed substitution16

The reaction is substantially accelerated in the pres-

ence of MeOH or other protic co-solvents

Scheme 4 Pd-catalyzed borylation of allylic alcohols

15c 15d

The Szaboacute group also developed palladium-catalyzed allylic C-H boryla-

tion methods17

These processes allowed for the synthesis of allylboronates

from readily available alkenes under oxidative conditions using BQ (1) or

the hypervalent iodonium salt

Ito Sawamura and their co-workers reported the regio- and stereoselec-

tive synthesis of allylboronates by Cu-catalyzed substitution of allyl

carbonates18

This method can also be extended to asymmetric catalysis for

the synthesis of enantioenriched allylboronates (Scheme 5)19

Scheme 5 Cu-catalyzed asymmetric borylation of allylcarbonates

19

Enantioselective synthesis of α-substituted allylboronates has been

reported by Hall and co-workers (Scheme 6)20

This method is based on

copper-catalyzed substitution of allylhalide substrates The chiral

allylboronates generated in this reaction were used for further transformation

without isolation

Scheme 6 Cu-catalyzed borylation reported by Hall and co-workers

20

Related Cu-catalyzed asymmetric synthesis of allylboronates have also

been independently reported by the groups of Hoveyda21

and McQuade22

Nickel-catalyzed stereospecific borylation of allylic acetates was developed

by Morken and co-workers23

The reaction is highly selective for the termi-

4

nal allylboronates (Scheme 7) The Morken group also developed palladi-

um-catalyzed enantioselective borylation methods for the synthesis of al-

lylboronates24

Scheme 7 Ni-catalyzed selective borylation of allylic acetates

23

Very recently Aggarwal and co-workers have reported a new method for

the preparation of enantioenriched allylboronates25

This so called ldquolithia-

tion-borylation methodrdquo involves homologation of vinyl boronates using

alkyl carbamates and butyllithium (BuLi) in the presence of (+)-sparteine

(Scheme 8)

Scheme 8 Synthesis of allylboronates by lithiation-borylation method

25b

As shown above synthesis of allylboron reagents has attracted large in-

terest in modern organic chemistry As a contribution to this field we devel-

oped a new method for the synthesis and isolation of allylboronic acids

which is presented in Chapter 3

13 Application of allylboronates in synthesis

Allylboronate reagents have been extensively used to synthesize numerous precursors for natural products and bioactive molecules

26

Addition of allylboronates to carbonyl and imine electrophiles is a well studied and documented reactions in synthetic organic chemistry

131 Stereoselective allylation of carbonyl compounds

Allylboration reactions of aldehydes have been widely applied for the ste-

reoselective synthesis of homoallylic alcohols3 After the discovery by Bub-

nov27

the reaction was further developed by Hoffmann28

Brown29

Roush30

and others Hoffmann and Brown carried out in depth mechanistic studies

which also explained the stereochemistry of the reaction Hoffman postulat-

ed that the reaction between allylboronates and aldehydes proceeds via a six-

5

membered cyclic TS similar to the Zimmerman-Traxler31

model (Scheme

9)28a 32

The high diastereoselectivity of the allylboration reaction is attributed to

an internal Lewis acid activation of the carbonyl functionality by the empty

p-orbital of boron

Scheme 9 Zimmerman-Traxler model to describe stereochemistry of allylboration

reaction

The addition of Lewis or Broslashnsted acids may accelerate the allylboration

of carbonyl compounds33

Hall and co-workers proposed that Lewis acids

coordinate to the lone pair of the boronate oxygen which renders the boron

atom more electron deficient (Scheme 10)33b 34

This mechanism for LA

and Broslashnsted acid activation was also confirmed by the DFT studies of

Houk and co-workers35

Scheme 10 Possible modes of Lewis acid activation for the allylboration

Allylboronates can also react with ketones yielding tertiary homoallylic

alcohols However the addition of allylboronates to ketones is much slower

than similar reactions with aldehydes Thus the selective allylation of

ketones with allylboronates often requires the use of catalysts36

In addition

most of the present methods for allylboration of ketones are limited to the

use of unsubstituted (parent) allylboronates or crotylboronates

132 Enantioselective allylation of carbonyl compounds

There are basically two main approaches for the asymmetric allylboration

of carbonyl compounds The first approach is the application of enantioen-

riched allylboronates performing chirality transfer and the second one is

6

asymmetric induction by using chiral catalyst One of the first asymmetric

allylboration reactions was reported by Roush and co-workers 13b 37

These

authors employed chiral auxiliaries attached to the boron atom (Scheme 11)

Diisopropyl tartrate (DIPT) proved to be a very efficient chiral auxiliary to

induce enantioselectivity

Scheme 11 Asymmetric allylation of aldehydes using chiral allylboronate

13b

A similar approach was reported by Soderquist and co-workers38

for the

asymmetric allylboration of aldehyde and ketones A bicyclic chiral auxilia-

ry on the boron atom was employed for highly diastereo- and enantioselec-

tive allylboration (Scheme 12)

Scheme 12 Diastereo-and enantioselective allylboration by chiral allylborane

38a

Enantiomerically pure TADDOL based allylboronates were developed by

Pietruszka and co-workers39

These reagents were used for chirality transfer

in allylboration of aldehydes (Scheme 13) The chiral auxiliary can be

recovered after the allylation by reduction with LiAlH4

Scheme 13 Asymmetric allylation of aldehyde using enantiopure allylboronate

39

Metal-catalyzed asymmetric synthesis of heterocyclic allylboronates was

described by Hall and co-workers40

These allylboronates were used in situ

for allylboration of aldehydes The key-step in synthesis of mefloquine was

performed using this method (Scheme 14)

7

Scheme 14 Asymmetric allylboration by cyclic allylboronates

40

Very recently Aggarwal and co-workers25b 41

reported an efficient

allylboration method using α-substituted enantioenriched allylboronates (see

also Scheme 8) The method is highly diastereo- and enantioselective In

addition the procedure is suitable for the synthesis of homoallylic alcohols

with two adjacent quaternary stereocenters (Scheme 15)

Scheme 15 Asymmetric allylation of ketone by α-substituted chiral allylboronate

25b

An alternative approach for the asymmetric allylboration of carbonyl

compounds involves the application of chiral catalysts Both Lewis and

Broslashnsted acids have been used for the asymmetric allylboration reactions

The first catalytic enantioselective allylboration reaction was reported by

Miyaura and co-workers (Scheme 16)33c

This reaction proceeded with a

high regio- and diastereoselectivity but the enantioselectivity was relatively

low

Scheme 16 Catalytic asymmetric allylboration of aldehyde

33c

Hall and co-workers42

reported a Sn-catalyzed asymmetric allylboration

reaction using allyl-Bpin as the allyl source A chiral diol was used as a lig-

and in this process which was supposed to coordinate to SnCl4 (Scheme 17)

8

Scheme 17 Tin-catalyzed asymmetric allylboration of aldehyde

42a

Asymmetric allylation of ketones was reported using chiral allylboronate

derived from BINOL compounds Chong and co-workers described the al-

lylation of ketones using 33-(CF3)2-BINOL boronate 3a (Scheme 18)43

The

reaction gave homoallylic alcohol product with a high level of enantioselec-

tivity

Scheme 18 Asymmetric allylation of ketone using BINOL-boronate

43

Catalytic methods have also been described to control both diastereo- and

enantioselectivity in the allylboration of ketones44

The first catalytic

enantioselective allylboration of ketones was developed by Shibasaki and

co-workers45

Broslashnsted acid such as BINOL derivatives44 46

was found to be

very efficient in the asymmetric allylboration reactions Schaus and

co-workers44

reported a method for asymmetric allylation of ketones using

isopropoxyboronate and catalytic amounts of Br2-BINOL 4a (Scheme 19)

Scheme 19 Catalytic asymmetric allylboration of ketone using Br2-BINOL

44a

These authors proposed a Zimmerman-Traxler type transition state to

rationalize the enantioselectivity in this reaction It has been also pointed out

that the substituent in BINOL (eg Br or CF3) has an important role for the

enantioselectivity of these reactions

Catalytic synthesis of homoallylic alcohols containing adjacent quater-

nary stereocenters has been a great challenge in synthetic organic chemistry

A new synthetic method for such reaction is presented in Section 52

9

133 Stereoselective allylation of imines

Homoallylic amine motifs occur in many natural products and biological-

ly relevant compounds47

One of the most common strategies for homoallylic

amine synthesis is the addition of allyl-metal reagents to imines48

The use of

allylboronate compounds for these reactions has emerged as an important

synthetic approach47

Allylboronates have a low toxicity high functional

group tolerance and the allylation of imines occurs with a high level of

selectivity

Stereoselective allylation of aldimines can be performed by

allylboronates in the presence of Lewis acid catalysts Batey and

co-workers49

reported the allylboration of N-toluenesulfonylimines using

crotyltrifluroboronate and BF3OEt2 (Scheme 20) The allylation was

proposed to proceed via the allyl-BF2 species which is generated from

allyl-BF3K

Scheme 20 Stereoselective allylation of imine by allyltrifluoroborate

49

Kobayashi and co-workers50

reported a three-component diastereoselec-

tive allylation reaction to synthesize homoallylic primary amines (Scheme

21) In addition several useful methods for asymmetric allylboration of

imines25b 51

using allylboronates can also be found in literature

Scheme 21 Synthesis of homoallylic amine using multicomponent method

50

Allylboration of acylhydrazones have also proven to be a very useful

reaction for the synthesis of homoallylic amine derivatives However the

allylation of acylhydrazones by allylboronates requires the application of

metal catalysts52

An indium-catalyzed reaction for the allylation of N-

acylhydrazone was reported by Kobayashi and co-workers (Scheme 22)52a

It

has been proposed that indium undergoes a transmetallation with allyl-Bpin

to form an active allyl-indium species which then added to the hydrazone

10

Scheme 22 Indium-catalyzed allylation of acylhydrazone

52a

We have developed a stereoselective method for allylation of imines and

acylhydrazones using allylboronic acids These results are summarized in

Chapter 6

11

2 Pd-catalyzed stereoselective allylic CminusH

trifluoroacetoxylation (Paper I)

As mentioned in the introduction transition metal-catalyzed CminusH bond activation methods have attracted increasing interest in organic synthesis

53

Using these methods multistep synthesis for prefunctionalization of the or-ganic substrates is not necessary In addition the waste production of the reaction can be reduced as the new functional group can be installed by re-placement of hydrogen

54 Palladium-catalyzed allylic CminusH bond activation is

one of the oldest and most versatile CminusH functionalization method (Section 11)

55 In this reaction (as in CminusH activation based processes in general) the

greatest challenge is the control of the regio- and stereoselectivity of the process

Stereodefined allylic acetates are very important precursors for regio- and stereoselective palladium-catalyzed allylic substitution reactions

56 Although

many regioselective allylic CminusH functionalization methods have been re-ported there are few reports on stereoselective allylic CminusH acetoxylation

7a

Most of these studies are intramolecular CminusH acyloxylation reactions For example a stereoselective allylic CminusH acetoxylation method has been re-ported by White and co-workers (Scheme 23) Intramolecular selectivity control allowed macrocyclization

57 and straightforward synthesis of anti-14-

dioxan-2-ones58

from simple olefins using Pd(II)sulfoxide catalysis Baumlck-vall and co-workers

59 have also developed several methods for the synthesis

of allylacetoxy compounds based on palladium-catalyzed intramolecular oxidative carbocyclization

Scheme 23 Stereoselective intramolecular CminusH oxidation reported by White and

co-workers58

12

21 Development of selective intermolecular allylic CminusH trifluoroacetoxylation

As our group previously developed a useful allylic CminusH acetoxylation

method based on using PhI(OAc)2 (2a) (see Section 11) as oxidant and ace-

tate source we envisioned that PhI(OCOCF3)2 (2b) can also be used in this

type of reaction to introduce a trifluoroacetate group at the allylic position of

alkenes Allylic trifluoroacetates are more reactive than allylic acetates in

transition metal-catalyzed substitutions60

and therefore an easy access to

these compounds is desirable As far as we know selective allylic CminusH tri-

fluoroacetoxylation has not been reported in the literature

In the early stage of development and optimization we employed car-

boxylated alkene 6a as our model substrate as it gave a high yield and ex-

hibited high selectivity in the Pd-catalyzed CminusH acetoxylation with 2a11b

However PhI(OCOCF3)2 (2b) is most likely a stronger oxidant than

PhI(OAc)2 (2a) and therefore we could not use oxidation sensitive solvents

such as THF or DMSO In addition the conjugated acid of the trifluoroace-

tate ion (the nucleophile) is a strong acid and therefore trifluoroacetic acid

could not be used as the solvent either After short optimization we have

found that dimethyl carbonate (DMC) is an excellent solvent for all reaction

components and it is not oxidized by PIFA We have found that the isolated

yields are higher when LiOCOCF3 is used as additive Under these condi-

tions the reaction could be performed with various functionalized alkenes

(Table 1)

13

Table 1 Pd-catalyzed allylic CminusH trifluoroacetoxylation of acyclic olefinsa

Both Pd(OAc)2 (5b) and Pd(OCOCF3)2 (5c) were equally efficient as cat-

alyst in the reaction So we decided to use 5b in the present synthetic method

as it is less expensive than 5c Not only terminal (6a) but internal alkenes

6b-c could also be used for trifluoroacetoxylation with high selectivity Oth-

er alkenes with electron withdrawing substituents such as 6d-e could also be

smoothly trifluoroacetoxylated Substrates without electron-withdrawing

groups gave intractable mixtures of trifluoroacetoxylated products For com-

pounds with long alkyl chain oxidation of the double bond occurred while in

the case of electron donating substituents mainly oxidation of the double

bond occurred together with other processes

14

Table 2 Stereoselective allylic CminusH trifluoroacetoxylation of cyclic alkenesa

Not only acyclic alkenes but cyclic alkenes could also be employed for

the trifluoroacetoxylation reaction Monosubstituted cyclic alkenes reacted

with a remarkably high selectivity (Table 2) The reaction conditions were

very similar to the trifluoroacetoxylation of acyclic substrates (Table 1) but

in order to get this high stereoselectivity the reactions had to be conducted

at 0 degC This is below the freezing point of DMC therefore the reaction me-

dium was diluted with DCM to avoid freezing of the reaction mixture The

yields with LiOCOCF3 were as high as in its absence therefore we did not

use this additive in the trifluoroacetoxylation of cyclic substrates

Considering the number of possible regio- and stereoisomers a mixture

of six allylic trifluoroacetate products could be expected Yet in most cases

we obtained a single diastereomer with very high regioselectivity (Table 2

entries 1-2 and 4-5) The major regioisomer in all cases was the 14-

substituted product (7f-j) with anti diastereoselectivity and the minor prod-

uct is the regioisomer of the same diastereomer The stereochemistry of the

major isomers was assigned based on NOE experiments

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

1 The ACS Style Guide 3rd ed Oxford University Press New York 2006

2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

3

certain Pd(II) pincer complexes are more efficient than Pd(dba)2 In depth

mechanistic studies revealed that catalytic amounts of Lewis or Broslashnsted

acids are required in the reaction to activate the allylic alcohols for Pd-

catalyzed substitution16

The reaction is substantially accelerated in the pres-

ence of MeOH or other protic co-solvents

Scheme 4 Pd-catalyzed borylation of allylic alcohols

15c 15d

The Szaboacute group also developed palladium-catalyzed allylic C-H boryla-

tion methods17

These processes allowed for the synthesis of allylboronates

from readily available alkenes under oxidative conditions using BQ (1) or

the hypervalent iodonium salt

Ito Sawamura and their co-workers reported the regio- and stereoselec-

tive synthesis of allylboronates by Cu-catalyzed substitution of allyl

carbonates18

This method can also be extended to asymmetric catalysis for

the synthesis of enantioenriched allylboronates (Scheme 5)19

Scheme 5 Cu-catalyzed asymmetric borylation of allylcarbonates

19

Enantioselective synthesis of α-substituted allylboronates has been

reported by Hall and co-workers (Scheme 6)20

This method is based on

copper-catalyzed substitution of allylhalide substrates The chiral

allylboronates generated in this reaction were used for further transformation

without isolation

Scheme 6 Cu-catalyzed borylation reported by Hall and co-workers

20

Related Cu-catalyzed asymmetric synthesis of allylboronates have also

been independently reported by the groups of Hoveyda21

and McQuade22

Nickel-catalyzed stereospecific borylation of allylic acetates was developed

by Morken and co-workers23

The reaction is highly selective for the termi-

4

nal allylboronates (Scheme 7) The Morken group also developed palladi-

um-catalyzed enantioselective borylation methods for the synthesis of al-

lylboronates24

Scheme 7 Ni-catalyzed selective borylation of allylic acetates

23

Very recently Aggarwal and co-workers have reported a new method for

the preparation of enantioenriched allylboronates25

This so called ldquolithia-

tion-borylation methodrdquo involves homologation of vinyl boronates using

alkyl carbamates and butyllithium (BuLi) in the presence of (+)-sparteine

(Scheme 8)

Scheme 8 Synthesis of allylboronates by lithiation-borylation method

25b

As shown above synthesis of allylboron reagents has attracted large in-

terest in modern organic chemistry As a contribution to this field we devel-

oped a new method for the synthesis and isolation of allylboronic acids

which is presented in Chapter 3

13 Application of allylboronates in synthesis

Allylboronate reagents have been extensively used to synthesize numerous precursors for natural products and bioactive molecules

26

Addition of allylboronates to carbonyl and imine electrophiles is a well studied and documented reactions in synthetic organic chemistry

131 Stereoselective allylation of carbonyl compounds

Allylboration reactions of aldehydes have been widely applied for the ste-

reoselective synthesis of homoallylic alcohols3 After the discovery by Bub-

nov27

the reaction was further developed by Hoffmann28

Brown29

Roush30

and others Hoffmann and Brown carried out in depth mechanistic studies

which also explained the stereochemistry of the reaction Hoffman postulat-

ed that the reaction between allylboronates and aldehydes proceeds via a six-

5

membered cyclic TS similar to the Zimmerman-Traxler31

model (Scheme

9)28a 32

The high diastereoselectivity of the allylboration reaction is attributed to

an internal Lewis acid activation of the carbonyl functionality by the empty

p-orbital of boron

Scheme 9 Zimmerman-Traxler model to describe stereochemistry of allylboration

reaction

The addition of Lewis or Broslashnsted acids may accelerate the allylboration

of carbonyl compounds33

Hall and co-workers proposed that Lewis acids

coordinate to the lone pair of the boronate oxygen which renders the boron

atom more electron deficient (Scheme 10)33b 34

This mechanism for LA

and Broslashnsted acid activation was also confirmed by the DFT studies of

Houk and co-workers35

Scheme 10 Possible modes of Lewis acid activation for the allylboration

Allylboronates can also react with ketones yielding tertiary homoallylic

alcohols However the addition of allylboronates to ketones is much slower

than similar reactions with aldehydes Thus the selective allylation of

ketones with allylboronates often requires the use of catalysts36

In addition

most of the present methods for allylboration of ketones are limited to the

use of unsubstituted (parent) allylboronates or crotylboronates

132 Enantioselective allylation of carbonyl compounds

There are basically two main approaches for the asymmetric allylboration

of carbonyl compounds The first approach is the application of enantioen-

riched allylboronates performing chirality transfer and the second one is

6

asymmetric induction by using chiral catalyst One of the first asymmetric

allylboration reactions was reported by Roush and co-workers 13b 37

These

authors employed chiral auxiliaries attached to the boron atom (Scheme 11)

Diisopropyl tartrate (DIPT) proved to be a very efficient chiral auxiliary to

induce enantioselectivity

Scheme 11 Asymmetric allylation of aldehydes using chiral allylboronate

13b

A similar approach was reported by Soderquist and co-workers38

for the

asymmetric allylboration of aldehyde and ketones A bicyclic chiral auxilia-

ry on the boron atom was employed for highly diastereo- and enantioselec-

tive allylboration (Scheme 12)

Scheme 12 Diastereo-and enantioselective allylboration by chiral allylborane

38a

Enantiomerically pure TADDOL based allylboronates were developed by

Pietruszka and co-workers39

These reagents were used for chirality transfer

in allylboration of aldehydes (Scheme 13) The chiral auxiliary can be

recovered after the allylation by reduction with LiAlH4

Scheme 13 Asymmetric allylation of aldehyde using enantiopure allylboronate

39

Metal-catalyzed asymmetric synthesis of heterocyclic allylboronates was

described by Hall and co-workers40

These allylboronates were used in situ

for allylboration of aldehydes The key-step in synthesis of mefloquine was

performed using this method (Scheme 14)

7

Scheme 14 Asymmetric allylboration by cyclic allylboronates

40

Very recently Aggarwal and co-workers25b 41

reported an efficient

allylboration method using α-substituted enantioenriched allylboronates (see

also Scheme 8) The method is highly diastereo- and enantioselective In

addition the procedure is suitable for the synthesis of homoallylic alcohols

with two adjacent quaternary stereocenters (Scheme 15)

Scheme 15 Asymmetric allylation of ketone by α-substituted chiral allylboronate

25b

An alternative approach for the asymmetric allylboration of carbonyl

compounds involves the application of chiral catalysts Both Lewis and

Broslashnsted acids have been used for the asymmetric allylboration reactions

The first catalytic enantioselective allylboration reaction was reported by

Miyaura and co-workers (Scheme 16)33c

This reaction proceeded with a

high regio- and diastereoselectivity but the enantioselectivity was relatively

low

Scheme 16 Catalytic asymmetric allylboration of aldehyde

33c

Hall and co-workers42

reported a Sn-catalyzed asymmetric allylboration

reaction using allyl-Bpin as the allyl source A chiral diol was used as a lig-

and in this process which was supposed to coordinate to SnCl4 (Scheme 17)

8

Scheme 17 Tin-catalyzed asymmetric allylboration of aldehyde

42a

Asymmetric allylation of ketones was reported using chiral allylboronate

derived from BINOL compounds Chong and co-workers described the al-

lylation of ketones using 33-(CF3)2-BINOL boronate 3a (Scheme 18)43

The

reaction gave homoallylic alcohol product with a high level of enantioselec-

tivity

Scheme 18 Asymmetric allylation of ketone using BINOL-boronate

43

Catalytic methods have also been described to control both diastereo- and

enantioselectivity in the allylboration of ketones44

The first catalytic

enantioselective allylboration of ketones was developed by Shibasaki and

co-workers45

Broslashnsted acid such as BINOL derivatives44 46

was found to be

very efficient in the asymmetric allylboration reactions Schaus and

co-workers44

reported a method for asymmetric allylation of ketones using

isopropoxyboronate and catalytic amounts of Br2-BINOL 4a (Scheme 19)

Scheme 19 Catalytic asymmetric allylboration of ketone using Br2-BINOL

44a

These authors proposed a Zimmerman-Traxler type transition state to

rationalize the enantioselectivity in this reaction It has been also pointed out

that the substituent in BINOL (eg Br or CF3) has an important role for the

enantioselectivity of these reactions

Catalytic synthesis of homoallylic alcohols containing adjacent quater-

nary stereocenters has been a great challenge in synthetic organic chemistry

A new synthetic method for such reaction is presented in Section 52

9

133 Stereoselective allylation of imines

Homoallylic amine motifs occur in many natural products and biological-

ly relevant compounds47

One of the most common strategies for homoallylic

amine synthesis is the addition of allyl-metal reagents to imines48

The use of

allylboronate compounds for these reactions has emerged as an important

synthetic approach47

Allylboronates have a low toxicity high functional

group tolerance and the allylation of imines occurs with a high level of

selectivity

Stereoselective allylation of aldimines can be performed by

allylboronates in the presence of Lewis acid catalysts Batey and

co-workers49

reported the allylboration of N-toluenesulfonylimines using

crotyltrifluroboronate and BF3OEt2 (Scheme 20) The allylation was

proposed to proceed via the allyl-BF2 species which is generated from

allyl-BF3K

Scheme 20 Stereoselective allylation of imine by allyltrifluoroborate

49

Kobayashi and co-workers50

reported a three-component diastereoselec-

tive allylation reaction to synthesize homoallylic primary amines (Scheme

21) In addition several useful methods for asymmetric allylboration of

imines25b 51

using allylboronates can also be found in literature

Scheme 21 Synthesis of homoallylic amine using multicomponent method

50

Allylboration of acylhydrazones have also proven to be a very useful

reaction for the synthesis of homoallylic amine derivatives However the

allylation of acylhydrazones by allylboronates requires the application of

metal catalysts52

An indium-catalyzed reaction for the allylation of N-

acylhydrazone was reported by Kobayashi and co-workers (Scheme 22)52a

It

has been proposed that indium undergoes a transmetallation with allyl-Bpin

to form an active allyl-indium species which then added to the hydrazone

10

Scheme 22 Indium-catalyzed allylation of acylhydrazone

52a

We have developed a stereoselective method for allylation of imines and

acylhydrazones using allylboronic acids These results are summarized in

Chapter 6

11

2 Pd-catalyzed stereoselective allylic CminusH

trifluoroacetoxylation (Paper I)

As mentioned in the introduction transition metal-catalyzed CminusH bond activation methods have attracted increasing interest in organic synthesis

53

Using these methods multistep synthesis for prefunctionalization of the or-ganic substrates is not necessary In addition the waste production of the reaction can be reduced as the new functional group can be installed by re-placement of hydrogen

54 Palladium-catalyzed allylic CminusH bond activation is

one of the oldest and most versatile CminusH functionalization method (Section 11)

55 In this reaction (as in CminusH activation based processes in general) the

greatest challenge is the control of the regio- and stereoselectivity of the process

Stereodefined allylic acetates are very important precursors for regio- and stereoselective palladium-catalyzed allylic substitution reactions

56 Although

many regioselective allylic CminusH functionalization methods have been re-ported there are few reports on stereoselective allylic CminusH acetoxylation

7a

Most of these studies are intramolecular CminusH acyloxylation reactions For example a stereoselective allylic CminusH acetoxylation method has been re-ported by White and co-workers (Scheme 23) Intramolecular selectivity control allowed macrocyclization

57 and straightforward synthesis of anti-14-

dioxan-2-ones58

from simple olefins using Pd(II)sulfoxide catalysis Baumlck-vall and co-workers

59 have also developed several methods for the synthesis

of allylacetoxy compounds based on palladium-catalyzed intramolecular oxidative carbocyclization

Scheme 23 Stereoselective intramolecular CminusH oxidation reported by White and

co-workers58

12

21 Development of selective intermolecular allylic CminusH trifluoroacetoxylation

As our group previously developed a useful allylic CminusH acetoxylation

method based on using PhI(OAc)2 (2a) (see Section 11) as oxidant and ace-

tate source we envisioned that PhI(OCOCF3)2 (2b) can also be used in this

type of reaction to introduce a trifluoroacetate group at the allylic position of

alkenes Allylic trifluoroacetates are more reactive than allylic acetates in

transition metal-catalyzed substitutions60

and therefore an easy access to

these compounds is desirable As far as we know selective allylic CminusH tri-

fluoroacetoxylation has not been reported in the literature

In the early stage of development and optimization we employed car-

boxylated alkene 6a as our model substrate as it gave a high yield and ex-

hibited high selectivity in the Pd-catalyzed CminusH acetoxylation with 2a11b

However PhI(OCOCF3)2 (2b) is most likely a stronger oxidant than

PhI(OAc)2 (2a) and therefore we could not use oxidation sensitive solvents

such as THF or DMSO In addition the conjugated acid of the trifluoroace-

tate ion (the nucleophile) is a strong acid and therefore trifluoroacetic acid

could not be used as the solvent either After short optimization we have

found that dimethyl carbonate (DMC) is an excellent solvent for all reaction

components and it is not oxidized by PIFA We have found that the isolated

yields are higher when LiOCOCF3 is used as additive Under these condi-

tions the reaction could be performed with various functionalized alkenes

(Table 1)

13

Table 1 Pd-catalyzed allylic CminusH trifluoroacetoxylation of acyclic olefinsa

Both Pd(OAc)2 (5b) and Pd(OCOCF3)2 (5c) were equally efficient as cat-

alyst in the reaction So we decided to use 5b in the present synthetic method

as it is less expensive than 5c Not only terminal (6a) but internal alkenes

6b-c could also be used for trifluoroacetoxylation with high selectivity Oth-

er alkenes with electron withdrawing substituents such as 6d-e could also be

smoothly trifluoroacetoxylated Substrates without electron-withdrawing

groups gave intractable mixtures of trifluoroacetoxylated products For com-

pounds with long alkyl chain oxidation of the double bond occurred while in

the case of electron donating substituents mainly oxidation of the double

bond occurred together with other processes

14

Table 2 Stereoselective allylic CminusH trifluoroacetoxylation of cyclic alkenesa

Not only acyclic alkenes but cyclic alkenes could also be employed for

the trifluoroacetoxylation reaction Monosubstituted cyclic alkenes reacted

with a remarkably high selectivity (Table 2) The reaction conditions were

very similar to the trifluoroacetoxylation of acyclic substrates (Table 1) but

in order to get this high stereoselectivity the reactions had to be conducted

at 0 degC This is below the freezing point of DMC therefore the reaction me-

dium was diluted with DCM to avoid freezing of the reaction mixture The

yields with LiOCOCF3 were as high as in its absence therefore we did not

use this additive in the trifluoroacetoxylation of cyclic substrates

Considering the number of possible regio- and stereoisomers a mixture

of six allylic trifluoroacetate products could be expected Yet in most cases

we obtained a single diastereomer with very high regioselectivity (Table 2

entries 1-2 and 4-5) The major regioisomer in all cases was the 14-

substituted product (7f-j) with anti diastereoselectivity and the minor prod-

uct is the regioisomer of the same diastereomer The stereochemistry of the

major isomers was assigned based on NOE experiments

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

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2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

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9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

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61

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12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

4

nal allylboronates (Scheme 7) The Morken group also developed palladi-

um-catalyzed enantioselective borylation methods for the synthesis of al-

lylboronates24

Scheme 7 Ni-catalyzed selective borylation of allylic acetates

23

Very recently Aggarwal and co-workers have reported a new method for

the preparation of enantioenriched allylboronates25

This so called ldquolithia-

tion-borylation methodrdquo involves homologation of vinyl boronates using

alkyl carbamates and butyllithium (BuLi) in the presence of (+)-sparteine

(Scheme 8)

Scheme 8 Synthesis of allylboronates by lithiation-borylation method

25b

As shown above synthesis of allylboron reagents has attracted large in-

terest in modern organic chemistry As a contribution to this field we devel-

oped a new method for the synthesis and isolation of allylboronic acids

which is presented in Chapter 3

13 Application of allylboronates in synthesis

Allylboronate reagents have been extensively used to synthesize numerous precursors for natural products and bioactive molecules

26

Addition of allylboronates to carbonyl and imine electrophiles is a well studied and documented reactions in synthetic organic chemistry

131 Stereoselective allylation of carbonyl compounds

Allylboration reactions of aldehydes have been widely applied for the ste-

reoselective synthesis of homoallylic alcohols3 After the discovery by Bub-

nov27

the reaction was further developed by Hoffmann28

Brown29

Roush30

and others Hoffmann and Brown carried out in depth mechanistic studies

which also explained the stereochemistry of the reaction Hoffman postulat-

ed that the reaction between allylboronates and aldehydes proceeds via a six-

5

membered cyclic TS similar to the Zimmerman-Traxler31

model (Scheme

9)28a 32

The high diastereoselectivity of the allylboration reaction is attributed to

an internal Lewis acid activation of the carbonyl functionality by the empty

p-orbital of boron

Scheme 9 Zimmerman-Traxler model to describe stereochemistry of allylboration

reaction

The addition of Lewis or Broslashnsted acids may accelerate the allylboration

of carbonyl compounds33

Hall and co-workers proposed that Lewis acids

coordinate to the lone pair of the boronate oxygen which renders the boron

atom more electron deficient (Scheme 10)33b 34

This mechanism for LA

and Broslashnsted acid activation was also confirmed by the DFT studies of

Houk and co-workers35

Scheme 10 Possible modes of Lewis acid activation for the allylboration

Allylboronates can also react with ketones yielding tertiary homoallylic

alcohols However the addition of allylboronates to ketones is much slower

than similar reactions with aldehydes Thus the selective allylation of

ketones with allylboronates often requires the use of catalysts36

In addition

most of the present methods for allylboration of ketones are limited to the

use of unsubstituted (parent) allylboronates or crotylboronates

132 Enantioselective allylation of carbonyl compounds

There are basically two main approaches for the asymmetric allylboration

of carbonyl compounds The first approach is the application of enantioen-

riched allylboronates performing chirality transfer and the second one is

6

asymmetric induction by using chiral catalyst One of the first asymmetric

allylboration reactions was reported by Roush and co-workers 13b 37

These

authors employed chiral auxiliaries attached to the boron atom (Scheme 11)

Diisopropyl tartrate (DIPT) proved to be a very efficient chiral auxiliary to

induce enantioselectivity

Scheme 11 Asymmetric allylation of aldehydes using chiral allylboronate

13b

A similar approach was reported by Soderquist and co-workers38

for the

asymmetric allylboration of aldehyde and ketones A bicyclic chiral auxilia-

ry on the boron atom was employed for highly diastereo- and enantioselec-

tive allylboration (Scheme 12)

Scheme 12 Diastereo-and enantioselective allylboration by chiral allylborane

38a

Enantiomerically pure TADDOL based allylboronates were developed by

Pietruszka and co-workers39

These reagents were used for chirality transfer

in allylboration of aldehydes (Scheme 13) The chiral auxiliary can be

recovered after the allylation by reduction with LiAlH4

Scheme 13 Asymmetric allylation of aldehyde using enantiopure allylboronate

39

Metal-catalyzed asymmetric synthesis of heterocyclic allylboronates was

described by Hall and co-workers40

These allylboronates were used in situ

for allylboration of aldehydes The key-step in synthesis of mefloquine was

performed using this method (Scheme 14)

7

Scheme 14 Asymmetric allylboration by cyclic allylboronates

40

Very recently Aggarwal and co-workers25b 41

reported an efficient

allylboration method using α-substituted enantioenriched allylboronates (see

also Scheme 8) The method is highly diastereo- and enantioselective In

addition the procedure is suitable for the synthesis of homoallylic alcohols

with two adjacent quaternary stereocenters (Scheme 15)

Scheme 15 Asymmetric allylation of ketone by α-substituted chiral allylboronate

25b

An alternative approach for the asymmetric allylboration of carbonyl

compounds involves the application of chiral catalysts Both Lewis and

Broslashnsted acids have been used for the asymmetric allylboration reactions

The first catalytic enantioselective allylboration reaction was reported by

Miyaura and co-workers (Scheme 16)33c

This reaction proceeded with a

high regio- and diastereoselectivity but the enantioselectivity was relatively

low

Scheme 16 Catalytic asymmetric allylboration of aldehyde

33c

Hall and co-workers42

reported a Sn-catalyzed asymmetric allylboration

reaction using allyl-Bpin as the allyl source A chiral diol was used as a lig-

and in this process which was supposed to coordinate to SnCl4 (Scheme 17)

8

Scheme 17 Tin-catalyzed asymmetric allylboration of aldehyde

42a

Asymmetric allylation of ketones was reported using chiral allylboronate

derived from BINOL compounds Chong and co-workers described the al-

lylation of ketones using 33-(CF3)2-BINOL boronate 3a (Scheme 18)43

The

reaction gave homoallylic alcohol product with a high level of enantioselec-

tivity

Scheme 18 Asymmetric allylation of ketone using BINOL-boronate

43

Catalytic methods have also been described to control both diastereo- and

enantioselectivity in the allylboration of ketones44

The first catalytic

enantioselective allylboration of ketones was developed by Shibasaki and

co-workers45

Broslashnsted acid such as BINOL derivatives44 46

was found to be

very efficient in the asymmetric allylboration reactions Schaus and

co-workers44

reported a method for asymmetric allylation of ketones using

isopropoxyboronate and catalytic amounts of Br2-BINOL 4a (Scheme 19)

Scheme 19 Catalytic asymmetric allylboration of ketone using Br2-BINOL

44a

These authors proposed a Zimmerman-Traxler type transition state to

rationalize the enantioselectivity in this reaction It has been also pointed out

that the substituent in BINOL (eg Br or CF3) has an important role for the

enantioselectivity of these reactions

Catalytic synthesis of homoallylic alcohols containing adjacent quater-

nary stereocenters has been a great challenge in synthetic organic chemistry

A new synthetic method for such reaction is presented in Section 52

9

133 Stereoselective allylation of imines

Homoallylic amine motifs occur in many natural products and biological-

ly relevant compounds47

One of the most common strategies for homoallylic

amine synthesis is the addition of allyl-metal reagents to imines48

The use of

allylboronate compounds for these reactions has emerged as an important

synthetic approach47

Allylboronates have a low toxicity high functional

group tolerance and the allylation of imines occurs with a high level of

selectivity

Stereoselective allylation of aldimines can be performed by

allylboronates in the presence of Lewis acid catalysts Batey and

co-workers49

reported the allylboration of N-toluenesulfonylimines using

crotyltrifluroboronate and BF3OEt2 (Scheme 20) The allylation was

proposed to proceed via the allyl-BF2 species which is generated from

allyl-BF3K

Scheme 20 Stereoselective allylation of imine by allyltrifluoroborate

49

Kobayashi and co-workers50

reported a three-component diastereoselec-

tive allylation reaction to synthesize homoallylic primary amines (Scheme

21) In addition several useful methods for asymmetric allylboration of

imines25b 51

using allylboronates can also be found in literature

Scheme 21 Synthesis of homoallylic amine using multicomponent method

50

Allylboration of acylhydrazones have also proven to be a very useful

reaction for the synthesis of homoallylic amine derivatives However the

allylation of acylhydrazones by allylboronates requires the application of

metal catalysts52

An indium-catalyzed reaction for the allylation of N-

acylhydrazone was reported by Kobayashi and co-workers (Scheme 22)52a

It

has been proposed that indium undergoes a transmetallation with allyl-Bpin

to form an active allyl-indium species which then added to the hydrazone

10

Scheme 22 Indium-catalyzed allylation of acylhydrazone

52a

We have developed a stereoselective method for allylation of imines and

acylhydrazones using allylboronic acids These results are summarized in

Chapter 6

11

2 Pd-catalyzed stereoselective allylic CminusH

trifluoroacetoxylation (Paper I)

As mentioned in the introduction transition metal-catalyzed CminusH bond activation methods have attracted increasing interest in organic synthesis

53

Using these methods multistep synthesis for prefunctionalization of the or-ganic substrates is not necessary In addition the waste production of the reaction can be reduced as the new functional group can be installed by re-placement of hydrogen

54 Palladium-catalyzed allylic CminusH bond activation is

one of the oldest and most versatile CminusH functionalization method (Section 11)

55 In this reaction (as in CminusH activation based processes in general) the

greatest challenge is the control of the regio- and stereoselectivity of the process

Stereodefined allylic acetates are very important precursors for regio- and stereoselective palladium-catalyzed allylic substitution reactions

56 Although

many regioselective allylic CminusH functionalization methods have been re-ported there are few reports on stereoselective allylic CminusH acetoxylation

7a

Most of these studies are intramolecular CminusH acyloxylation reactions For example a stereoselective allylic CminusH acetoxylation method has been re-ported by White and co-workers (Scheme 23) Intramolecular selectivity control allowed macrocyclization

57 and straightforward synthesis of anti-14-

dioxan-2-ones58

from simple olefins using Pd(II)sulfoxide catalysis Baumlck-vall and co-workers

59 have also developed several methods for the synthesis

of allylacetoxy compounds based on palladium-catalyzed intramolecular oxidative carbocyclization

Scheme 23 Stereoselective intramolecular CminusH oxidation reported by White and

co-workers58

12

21 Development of selective intermolecular allylic CminusH trifluoroacetoxylation

As our group previously developed a useful allylic CminusH acetoxylation

method based on using PhI(OAc)2 (2a) (see Section 11) as oxidant and ace-

tate source we envisioned that PhI(OCOCF3)2 (2b) can also be used in this

type of reaction to introduce a trifluoroacetate group at the allylic position of

alkenes Allylic trifluoroacetates are more reactive than allylic acetates in

transition metal-catalyzed substitutions60

and therefore an easy access to

these compounds is desirable As far as we know selective allylic CminusH tri-

fluoroacetoxylation has not been reported in the literature

In the early stage of development and optimization we employed car-

boxylated alkene 6a as our model substrate as it gave a high yield and ex-

hibited high selectivity in the Pd-catalyzed CminusH acetoxylation with 2a11b

However PhI(OCOCF3)2 (2b) is most likely a stronger oxidant than

PhI(OAc)2 (2a) and therefore we could not use oxidation sensitive solvents

such as THF or DMSO In addition the conjugated acid of the trifluoroace-

tate ion (the nucleophile) is a strong acid and therefore trifluoroacetic acid

could not be used as the solvent either After short optimization we have

found that dimethyl carbonate (DMC) is an excellent solvent for all reaction

components and it is not oxidized by PIFA We have found that the isolated

yields are higher when LiOCOCF3 is used as additive Under these condi-

tions the reaction could be performed with various functionalized alkenes

(Table 1)

13

Table 1 Pd-catalyzed allylic CminusH trifluoroacetoxylation of acyclic olefinsa

Both Pd(OAc)2 (5b) and Pd(OCOCF3)2 (5c) were equally efficient as cat-

alyst in the reaction So we decided to use 5b in the present synthetic method

as it is less expensive than 5c Not only terminal (6a) but internal alkenes

6b-c could also be used for trifluoroacetoxylation with high selectivity Oth-

er alkenes with electron withdrawing substituents such as 6d-e could also be

smoothly trifluoroacetoxylated Substrates without electron-withdrawing

groups gave intractable mixtures of trifluoroacetoxylated products For com-

pounds with long alkyl chain oxidation of the double bond occurred while in

the case of electron donating substituents mainly oxidation of the double

bond occurred together with other processes

14

Table 2 Stereoselective allylic CminusH trifluoroacetoxylation of cyclic alkenesa

Not only acyclic alkenes but cyclic alkenes could also be employed for

the trifluoroacetoxylation reaction Monosubstituted cyclic alkenes reacted

with a remarkably high selectivity (Table 2) The reaction conditions were

very similar to the trifluoroacetoxylation of acyclic substrates (Table 1) but

in order to get this high stereoselectivity the reactions had to be conducted

at 0 degC This is below the freezing point of DMC therefore the reaction me-

dium was diluted with DCM to avoid freezing of the reaction mixture The

yields with LiOCOCF3 were as high as in its absence therefore we did not

use this additive in the trifluoroacetoxylation of cyclic substrates

Considering the number of possible regio- and stereoisomers a mixture

of six allylic trifluoroacetate products could be expected Yet in most cases

we obtained a single diastereomer with very high regioselectivity (Table 2

entries 1-2 and 4-5) The major regioisomer in all cases was the 14-

substituted product (7f-j) with anti diastereoselectivity and the minor prod-

uct is the regioisomer of the same diastereomer The stereochemistry of the

major isomers was assigned based on NOE experiments

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

5

membered cyclic TS similar to the Zimmerman-Traxler31

model (Scheme

9)28a 32

The high diastereoselectivity of the allylboration reaction is attributed to

an internal Lewis acid activation of the carbonyl functionality by the empty

p-orbital of boron

Scheme 9 Zimmerman-Traxler model to describe stereochemistry of allylboration

reaction

The addition of Lewis or Broslashnsted acids may accelerate the allylboration

of carbonyl compounds33

Hall and co-workers proposed that Lewis acids

coordinate to the lone pair of the boronate oxygen which renders the boron

atom more electron deficient (Scheme 10)33b 34

This mechanism for LA

and Broslashnsted acid activation was also confirmed by the DFT studies of

Houk and co-workers35

Scheme 10 Possible modes of Lewis acid activation for the allylboration

Allylboronates can also react with ketones yielding tertiary homoallylic

alcohols However the addition of allylboronates to ketones is much slower

than similar reactions with aldehydes Thus the selective allylation of

ketones with allylboronates often requires the use of catalysts36

In addition

most of the present methods for allylboration of ketones are limited to the

use of unsubstituted (parent) allylboronates or crotylboronates

132 Enantioselective allylation of carbonyl compounds

There are basically two main approaches for the asymmetric allylboration

of carbonyl compounds The first approach is the application of enantioen-

riched allylboronates performing chirality transfer and the second one is

6

asymmetric induction by using chiral catalyst One of the first asymmetric

allylboration reactions was reported by Roush and co-workers 13b 37

These

authors employed chiral auxiliaries attached to the boron atom (Scheme 11)

Diisopropyl tartrate (DIPT) proved to be a very efficient chiral auxiliary to

induce enantioselectivity

Scheme 11 Asymmetric allylation of aldehydes using chiral allylboronate

13b

A similar approach was reported by Soderquist and co-workers38

for the

asymmetric allylboration of aldehyde and ketones A bicyclic chiral auxilia-

ry on the boron atom was employed for highly diastereo- and enantioselec-

tive allylboration (Scheme 12)

Scheme 12 Diastereo-and enantioselective allylboration by chiral allylborane

38a

Enantiomerically pure TADDOL based allylboronates were developed by

Pietruszka and co-workers39

These reagents were used for chirality transfer

in allylboration of aldehydes (Scheme 13) The chiral auxiliary can be

recovered after the allylation by reduction with LiAlH4

Scheme 13 Asymmetric allylation of aldehyde using enantiopure allylboronate

39

Metal-catalyzed asymmetric synthesis of heterocyclic allylboronates was

described by Hall and co-workers40

These allylboronates were used in situ

for allylboration of aldehydes The key-step in synthesis of mefloquine was

performed using this method (Scheme 14)

7

Scheme 14 Asymmetric allylboration by cyclic allylboronates

40

Very recently Aggarwal and co-workers25b 41

reported an efficient

allylboration method using α-substituted enantioenriched allylboronates (see

also Scheme 8) The method is highly diastereo- and enantioselective In

addition the procedure is suitable for the synthesis of homoallylic alcohols

with two adjacent quaternary stereocenters (Scheme 15)

Scheme 15 Asymmetric allylation of ketone by α-substituted chiral allylboronate

25b

An alternative approach for the asymmetric allylboration of carbonyl

compounds involves the application of chiral catalysts Both Lewis and

Broslashnsted acids have been used for the asymmetric allylboration reactions

The first catalytic enantioselective allylboration reaction was reported by

Miyaura and co-workers (Scheme 16)33c

This reaction proceeded with a

high regio- and diastereoselectivity but the enantioselectivity was relatively

low

Scheme 16 Catalytic asymmetric allylboration of aldehyde

33c

Hall and co-workers42

reported a Sn-catalyzed asymmetric allylboration

reaction using allyl-Bpin as the allyl source A chiral diol was used as a lig-

and in this process which was supposed to coordinate to SnCl4 (Scheme 17)

8

Scheme 17 Tin-catalyzed asymmetric allylboration of aldehyde

42a

Asymmetric allylation of ketones was reported using chiral allylboronate

derived from BINOL compounds Chong and co-workers described the al-

lylation of ketones using 33-(CF3)2-BINOL boronate 3a (Scheme 18)43

The

reaction gave homoallylic alcohol product with a high level of enantioselec-

tivity

Scheme 18 Asymmetric allylation of ketone using BINOL-boronate

43

Catalytic methods have also been described to control both diastereo- and

enantioselectivity in the allylboration of ketones44

The first catalytic

enantioselective allylboration of ketones was developed by Shibasaki and

co-workers45

Broslashnsted acid such as BINOL derivatives44 46

was found to be

very efficient in the asymmetric allylboration reactions Schaus and

co-workers44

reported a method for asymmetric allylation of ketones using

isopropoxyboronate and catalytic amounts of Br2-BINOL 4a (Scheme 19)

Scheme 19 Catalytic asymmetric allylboration of ketone using Br2-BINOL

44a

These authors proposed a Zimmerman-Traxler type transition state to

rationalize the enantioselectivity in this reaction It has been also pointed out

that the substituent in BINOL (eg Br or CF3) has an important role for the

enantioselectivity of these reactions

Catalytic synthesis of homoallylic alcohols containing adjacent quater-

nary stereocenters has been a great challenge in synthetic organic chemistry

A new synthetic method for such reaction is presented in Section 52

9

133 Stereoselective allylation of imines

Homoallylic amine motifs occur in many natural products and biological-

ly relevant compounds47

One of the most common strategies for homoallylic

amine synthesis is the addition of allyl-metal reagents to imines48

The use of

allylboronate compounds for these reactions has emerged as an important

synthetic approach47

Allylboronates have a low toxicity high functional

group tolerance and the allylation of imines occurs with a high level of

selectivity

Stereoselective allylation of aldimines can be performed by

allylboronates in the presence of Lewis acid catalysts Batey and

co-workers49

reported the allylboration of N-toluenesulfonylimines using

crotyltrifluroboronate and BF3OEt2 (Scheme 20) The allylation was

proposed to proceed via the allyl-BF2 species which is generated from

allyl-BF3K

Scheme 20 Stereoselective allylation of imine by allyltrifluoroborate

49

Kobayashi and co-workers50

reported a three-component diastereoselec-

tive allylation reaction to synthesize homoallylic primary amines (Scheme

21) In addition several useful methods for asymmetric allylboration of

imines25b 51

using allylboronates can also be found in literature

Scheme 21 Synthesis of homoallylic amine using multicomponent method

50

Allylboration of acylhydrazones have also proven to be a very useful

reaction for the synthesis of homoallylic amine derivatives However the

allylation of acylhydrazones by allylboronates requires the application of

metal catalysts52

An indium-catalyzed reaction for the allylation of N-

acylhydrazone was reported by Kobayashi and co-workers (Scheme 22)52a

It

has been proposed that indium undergoes a transmetallation with allyl-Bpin

to form an active allyl-indium species which then added to the hydrazone

10

Scheme 22 Indium-catalyzed allylation of acylhydrazone

52a

We have developed a stereoselective method for allylation of imines and

acylhydrazones using allylboronic acids These results are summarized in

Chapter 6

11

2 Pd-catalyzed stereoselective allylic CminusH

trifluoroacetoxylation (Paper I)

As mentioned in the introduction transition metal-catalyzed CminusH bond activation methods have attracted increasing interest in organic synthesis

53

Using these methods multistep synthesis for prefunctionalization of the or-ganic substrates is not necessary In addition the waste production of the reaction can be reduced as the new functional group can be installed by re-placement of hydrogen

54 Palladium-catalyzed allylic CminusH bond activation is

one of the oldest and most versatile CminusH functionalization method (Section 11)

55 In this reaction (as in CminusH activation based processes in general) the

greatest challenge is the control of the regio- and stereoselectivity of the process

Stereodefined allylic acetates are very important precursors for regio- and stereoselective palladium-catalyzed allylic substitution reactions

56 Although

many regioselective allylic CminusH functionalization methods have been re-ported there are few reports on stereoselective allylic CminusH acetoxylation

7a

Most of these studies are intramolecular CminusH acyloxylation reactions For example a stereoselective allylic CminusH acetoxylation method has been re-ported by White and co-workers (Scheme 23) Intramolecular selectivity control allowed macrocyclization

57 and straightforward synthesis of anti-14-

dioxan-2-ones58

from simple olefins using Pd(II)sulfoxide catalysis Baumlck-vall and co-workers

59 have also developed several methods for the synthesis

of allylacetoxy compounds based on palladium-catalyzed intramolecular oxidative carbocyclization

Scheme 23 Stereoselective intramolecular CminusH oxidation reported by White and

co-workers58

12

21 Development of selective intermolecular allylic CminusH trifluoroacetoxylation

As our group previously developed a useful allylic CminusH acetoxylation

method based on using PhI(OAc)2 (2a) (see Section 11) as oxidant and ace-

tate source we envisioned that PhI(OCOCF3)2 (2b) can also be used in this

type of reaction to introduce a trifluoroacetate group at the allylic position of

alkenes Allylic trifluoroacetates are more reactive than allylic acetates in

transition metal-catalyzed substitutions60

and therefore an easy access to

these compounds is desirable As far as we know selective allylic CminusH tri-

fluoroacetoxylation has not been reported in the literature

In the early stage of development and optimization we employed car-

boxylated alkene 6a as our model substrate as it gave a high yield and ex-

hibited high selectivity in the Pd-catalyzed CminusH acetoxylation with 2a11b

However PhI(OCOCF3)2 (2b) is most likely a stronger oxidant than

PhI(OAc)2 (2a) and therefore we could not use oxidation sensitive solvents

such as THF or DMSO In addition the conjugated acid of the trifluoroace-

tate ion (the nucleophile) is a strong acid and therefore trifluoroacetic acid

could not be used as the solvent either After short optimization we have

found that dimethyl carbonate (DMC) is an excellent solvent for all reaction

components and it is not oxidized by PIFA We have found that the isolated

yields are higher when LiOCOCF3 is used as additive Under these condi-

tions the reaction could be performed with various functionalized alkenes

(Table 1)

13

Table 1 Pd-catalyzed allylic CminusH trifluoroacetoxylation of acyclic olefinsa

Both Pd(OAc)2 (5b) and Pd(OCOCF3)2 (5c) were equally efficient as cat-

alyst in the reaction So we decided to use 5b in the present synthetic method

as it is less expensive than 5c Not only terminal (6a) but internal alkenes

6b-c could also be used for trifluoroacetoxylation with high selectivity Oth-

er alkenes with electron withdrawing substituents such as 6d-e could also be

smoothly trifluoroacetoxylated Substrates without electron-withdrawing

groups gave intractable mixtures of trifluoroacetoxylated products For com-

pounds with long alkyl chain oxidation of the double bond occurred while in

the case of electron donating substituents mainly oxidation of the double

bond occurred together with other processes

14

Table 2 Stereoselective allylic CminusH trifluoroacetoxylation of cyclic alkenesa

Not only acyclic alkenes but cyclic alkenes could also be employed for

the trifluoroacetoxylation reaction Monosubstituted cyclic alkenes reacted

with a remarkably high selectivity (Table 2) The reaction conditions were

very similar to the trifluoroacetoxylation of acyclic substrates (Table 1) but

in order to get this high stereoselectivity the reactions had to be conducted

at 0 degC This is below the freezing point of DMC therefore the reaction me-

dium was diluted with DCM to avoid freezing of the reaction mixture The

yields with LiOCOCF3 were as high as in its absence therefore we did not

use this additive in the trifluoroacetoxylation of cyclic substrates

Considering the number of possible regio- and stereoisomers a mixture

of six allylic trifluoroacetate products could be expected Yet in most cases

we obtained a single diastereomer with very high regioselectivity (Table 2

entries 1-2 and 4-5) The major regioisomer in all cases was the 14-

substituted product (7f-j) with anti diastereoselectivity and the minor prod-

uct is the regioisomer of the same diastereomer The stereochemistry of the

major isomers was assigned based on NOE experiments

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

6

asymmetric induction by using chiral catalyst One of the first asymmetric

allylboration reactions was reported by Roush and co-workers 13b 37

These

authors employed chiral auxiliaries attached to the boron atom (Scheme 11)

Diisopropyl tartrate (DIPT) proved to be a very efficient chiral auxiliary to

induce enantioselectivity

Scheme 11 Asymmetric allylation of aldehydes using chiral allylboronate

13b

A similar approach was reported by Soderquist and co-workers38

for the

asymmetric allylboration of aldehyde and ketones A bicyclic chiral auxilia-

ry on the boron atom was employed for highly diastereo- and enantioselec-

tive allylboration (Scheme 12)

Scheme 12 Diastereo-and enantioselective allylboration by chiral allylborane

38a

Enantiomerically pure TADDOL based allylboronates were developed by

Pietruszka and co-workers39

These reagents were used for chirality transfer

in allylboration of aldehydes (Scheme 13) The chiral auxiliary can be

recovered after the allylation by reduction with LiAlH4

Scheme 13 Asymmetric allylation of aldehyde using enantiopure allylboronate

39

Metal-catalyzed asymmetric synthesis of heterocyclic allylboronates was

described by Hall and co-workers40

These allylboronates were used in situ

for allylboration of aldehydes The key-step in synthesis of mefloquine was

performed using this method (Scheme 14)

7

Scheme 14 Asymmetric allylboration by cyclic allylboronates

40

Very recently Aggarwal and co-workers25b 41

reported an efficient

allylboration method using α-substituted enantioenriched allylboronates (see

also Scheme 8) The method is highly diastereo- and enantioselective In

addition the procedure is suitable for the synthesis of homoallylic alcohols

with two adjacent quaternary stereocenters (Scheme 15)

Scheme 15 Asymmetric allylation of ketone by α-substituted chiral allylboronate

25b

An alternative approach for the asymmetric allylboration of carbonyl

compounds involves the application of chiral catalysts Both Lewis and

Broslashnsted acids have been used for the asymmetric allylboration reactions

The first catalytic enantioselective allylboration reaction was reported by

Miyaura and co-workers (Scheme 16)33c

This reaction proceeded with a

high regio- and diastereoselectivity but the enantioselectivity was relatively

low

Scheme 16 Catalytic asymmetric allylboration of aldehyde

33c

Hall and co-workers42

reported a Sn-catalyzed asymmetric allylboration

reaction using allyl-Bpin as the allyl source A chiral diol was used as a lig-

and in this process which was supposed to coordinate to SnCl4 (Scheme 17)

8

Scheme 17 Tin-catalyzed asymmetric allylboration of aldehyde

42a

Asymmetric allylation of ketones was reported using chiral allylboronate

derived from BINOL compounds Chong and co-workers described the al-

lylation of ketones using 33-(CF3)2-BINOL boronate 3a (Scheme 18)43

The

reaction gave homoallylic alcohol product with a high level of enantioselec-

tivity

Scheme 18 Asymmetric allylation of ketone using BINOL-boronate

43

Catalytic methods have also been described to control both diastereo- and

enantioselectivity in the allylboration of ketones44

The first catalytic

enantioselective allylboration of ketones was developed by Shibasaki and

co-workers45

Broslashnsted acid such as BINOL derivatives44 46

was found to be

very efficient in the asymmetric allylboration reactions Schaus and

co-workers44

reported a method for asymmetric allylation of ketones using

isopropoxyboronate and catalytic amounts of Br2-BINOL 4a (Scheme 19)

Scheme 19 Catalytic asymmetric allylboration of ketone using Br2-BINOL

44a

These authors proposed a Zimmerman-Traxler type transition state to

rationalize the enantioselectivity in this reaction It has been also pointed out

that the substituent in BINOL (eg Br or CF3) has an important role for the

enantioselectivity of these reactions

Catalytic synthesis of homoallylic alcohols containing adjacent quater-

nary stereocenters has been a great challenge in synthetic organic chemistry

A new synthetic method for such reaction is presented in Section 52

9

133 Stereoselective allylation of imines

Homoallylic amine motifs occur in many natural products and biological-

ly relevant compounds47

One of the most common strategies for homoallylic

amine synthesis is the addition of allyl-metal reagents to imines48

The use of

allylboronate compounds for these reactions has emerged as an important

synthetic approach47

Allylboronates have a low toxicity high functional

group tolerance and the allylation of imines occurs with a high level of

selectivity

Stereoselective allylation of aldimines can be performed by

allylboronates in the presence of Lewis acid catalysts Batey and

co-workers49

reported the allylboration of N-toluenesulfonylimines using

crotyltrifluroboronate and BF3OEt2 (Scheme 20) The allylation was

proposed to proceed via the allyl-BF2 species which is generated from

allyl-BF3K

Scheme 20 Stereoselective allylation of imine by allyltrifluoroborate

49

Kobayashi and co-workers50

reported a three-component diastereoselec-

tive allylation reaction to synthesize homoallylic primary amines (Scheme

21) In addition several useful methods for asymmetric allylboration of

imines25b 51

using allylboronates can also be found in literature

Scheme 21 Synthesis of homoallylic amine using multicomponent method

50

Allylboration of acylhydrazones have also proven to be a very useful

reaction for the synthesis of homoallylic amine derivatives However the

allylation of acylhydrazones by allylboronates requires the application of

metal catalysts52

An indium-catalyzed reaction for the allylation of N-

acylhydrazone was reported by Kobayashi and co-workers (Scheme 22)52a

It

has been proposed that indium undergoes a transmetallation with allyl-Bpin

to form an active allyl-indium species which then added to the hydrazone

10

Scheme 22 Indium-catalyzed allylation of acylhydrazone

52a

We have developed a stereoselective method for allylation of imines and

acylhydrazones using allylboronic acids These results are summarized in

Chapter 6

11

2 Pd-catalyzed stereoselective allylic CminusH

trifluoroacetoxylation (Paper I)

As mentioned in the introduction transition metal-catalyzed CminusH bond activation methods have attracted increasing interest in organic synthesis

53

Using these methods multistep synthesis for prefunctionalization of the or-ganic substrates is not necessary In addition the waste production of the reaction can be reduced as the new functional group can be installed by re-placement of hydrogen

54 Palladium-catalyzed allylic CminusH bond activation is

one of the oldest and most versatile CminusH functionalization method (Section 11)

55 In this reaction (as in CminusH activation based processes in general) the

greatest challenge is the control of the regio- and stereoselectivity of the process

Stereodefined allylic acetates are very important precursors for regio- and stereoselective palladium-catalyzed allylic substitution reactions

56 Although

many regioselective allylic CminusH functionalization methods have been re-ported there are few reports on stereoselective allylic CminusH acetoxylation

7a

Most of these studies are intramolecular CminusH acyloxylation reactions For example a stereoselective allylic CminusH acetoxylation method has been re-ported by White and co-workers (Scheme 23) Intramolecular selectivity control allowed macrocyclization

57 and straightforward synthesis of anti-14-

dioxan-2-ones58

from simple olefins using Pd(II)sulfoxide catalysis Baumlck-vall and co-workers

59 have also developed several methods for the synthesis

of allylacetoxy compounds based on palladium-catalyzed intramolecular oxidative carbocyclization

Scheme 23 Stereoselective intramolecular CminusH oxidation reported by White and

co-workers58

12

21 Development of selective intermolecular allylic CminusH trifluoroacetoxylation

As our group previously developed a useful allylic CminusH acetoxylation

method based on using PhI(OAc)2 (2a) (see Section 11) as oxidant and ace-

tate source we envisioned that PhI(OCOCF3)2 (2b) can also be used in this

type of reaction to introduce a trifluoroacetate group at the allylic position of

alkenes Allylic trifluoroacetates are more reactive than allylic acetates in

transition metal-catalyzed substitutions60

and therefore an easy access to

these compounds is desirable As far as we know selective allylic CminusH tri-

fluoroacetoxylation has not been reported in the literature

In the early stage of development and optimization we employed car-

boxylated alkene 6a as our model substrate as it gave a high yield and ex-

hibited high selectivity in the Pd-catalyzed CminusH acetoxylation with 2a11b

However PhI(OCOCF3)2 (2b) is most likely a stronger oxidant than

PhI(OAc)2 (2a) and therefore we could not use oxidation sensitive solvents

such as THF or DMSO In addition the conjugated acid of the trifluoroace-

tate ion (the nucleophile) is a strong acid and therefore trifluoroacetic acid

could not be used as the solvent either After short optimization we have

found that dimethyl carbonate (DMC) is an excellent solvent for all reaction

components and it is not oxidized by PIFA We have found that the isolated

yields are higher when LiOCOCF3 is used as additive Under these condi-

tions the reaction could be performed with various functionalized alkenes

(Table 1)

13

Table 1 Pd-catalyzed allylic CminusH trifluoroacetoxylation of acyclic olefinsa

Both Pd(OAc)2 (5b) and Pd(OCOCF3)2 (5c) were equally efficient as cat-

alyst in the reaction So we decided to use 5b in the present synthetic method

as it is less expensive than 5c Not only terminal (6a) but internal alkenes

6b-c could also be used for trifluoroacetoxylation with high selectivity Oth-

er alkenes with electron withdrawing substituents such as 6d-e could also be

smoothly trifluoroacetoxylated Substrates without electron-withdrawing

groups gave intractable mixtures of trifluoroacetoxylated products For com-

pounds with long alkyl chain oxidation of the double bond occurred while in

the case of electron donating substituents mainly oxidation of the double

bond occurred together with other processes

14

Table 2 Stereoselective allylic CminusH trifluoroacetoxylation of cyclic alkenesa

Not only acyclic alkenes but cyclic alkenes could also be employed for

the trifluoroacetoxylation reaction Monosubstituted cyclic alkenes reacted

with a remarkably high selectivity (Table 2) The reaction conditions were

very similar to the trifluoroacetoxylation of acyclic substrates (Table 1) but

in order to get this high stereoselectivity the reactions had to be conducted

at 0 degC This is below the freezing point of DMC therefore the reaction me-

dium was diluted with DCM to avoid freezing of the reaction mixture The

yields with LiOCOCF3 were as high as in its absence therefore we did not

use this additive in the trifluoroacetoxylation of cyclic substrates

Considering the number of possible regio- and stereoisomers a mixture

of six allylic trifluoroacetate products could be expected Yet in most cases

we obtained a single diastereomer with very high regioselectivity (Table 2

entries 1-2 and 4-5) The major regioisomer in all cases was the 14-

substituted product (7f-j) with anti diastereoselectivity and the minor prod-

uct is the regioisomer of the same diastereomer The stereochemistry of the

major isomers was assigned based on NOE experiments

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

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12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

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14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

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16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

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20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

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1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

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11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

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45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

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67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

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72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

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1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

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80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

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83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

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86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

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88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

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91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

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94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

7

Scheme 14 Asymmetric allylboration by cyclic allylboronates

40

Very recently Aggarwal and co-workers25b 41

reported an efficient

allylboration method using α-substituted enantioenriched allylboronates (see

also Scheme 8) The method is highly diastereo- and enantioselective In

addition the procedure is suitable for the synthesis of homoallylic alcohols

with two adjacent quaternary stereocenters (Scheme 15)

Scheme 15 Asymmetric allylation of ketone by α-substituted chiral allylboronate

25b

An alternative approach for the asymmetric allylboration of carbonyl

compounds involves the application of chiral catalysts Both Lewis and

Broslashnsted acids have been used for the asymmetric allylboration reactions

The first catalytic enantioselective allylboration reaction was reported by

Miyaura and co-workers (Scheme 16)33c

This reaction proceeded with a

high regio- and diastereoselectivity but the enantioselectivity was relatively

low

Scheme 16 Catalytic asymmetric allylboration of aldehyde

33c

Hall and co-workers42

reported a Sn-catalyzed asymmetric allylboration

reaction using allyl-Bpin as the allyl source A chiral diol was used as a lig-

and in this process which was supposed to coordinate to SnCl4 (Scheme 17)

8

Scheme 17 Tin-catalyzed asymmetric allylboration of aldehyde

42a

Asymmetric allylation of ketones was reported using chiral allylboronate

derived from BINOL compounds Chong and co-workers described the al-

lylation of ketones using 33-(CF3)2-BINOL boronate 3a (Scheme 18)43

The

reaction gave homoallylic alcohol product with a high level of enantioselec-

tivity

Scheme 18 Asymmetric allylation of ketone using BINOL-boronate

43

Catalytic methods have also been described to control both diastereo- and

enantioselectivity in the allylboration of ketones44

The first catalytic

enantioselective allylboration of ketones was developed by Shibasaki and

co-workers45

Broslashnsted acid such as BINOL derivatives44 46

was found to be

very efficient in the asymmetric allylboration reactions Schaus and

co-workers44

reported a method for asymmetric allylation of ketones using

isopropoxyboronate and catalytic amounts of Br2-BINOL 4a (Scheme 19)

Scheme 19 Catalytic asymmetric allylboration of ketone using Br2-BINOL

44a

These authors proposed a Zimmerman-Traxler type transition state to

rationalize the enantioselectivity in this reaction It has been also pointed out

that the substituent in BINOL (eg Br or CF3) has an important role for the

enantioselectivity of these reactions

Catalytic synthesis of homoallylic alcohols containing adjacent quater-

nary stereocenters has been a great challenge in synthetic organic chemistry

A new synthetic method for such reaction is presented in Section 52

9

133 Stereoselective allylation of imines

Homoallylic amine motifs occur in many natural products and biological-

ly relevant compounds47

One of the most common strategies for homoallylic

amine synthesis is the addition of allyl-metal reagents to imines48

The use of

allylboronate compounds for these reactions has emerged as an important

synthetic approach47

Allylboronates have a low toxicity high functional

group tolerance and the allylation of imines occurs with a high level of

selectivity

Stereoselective allylation of aldimines can be performed by

allylboronates in the presence of Lewis acid catalysts Batey and

co-workers49

reported the allylboration of N-toluenesulfonylimines using

crotyltrifluroboronate and BF3OEt2 (Scheme 20) The allylation was

proposed to proceed via the allyl-BF2 species which is generated from

allyl-BF3K

Scheme 20 Stereoselective allylation of imine by allyltrifluoroborate

49

Kobayashi and co-workers50

reported a three-component diastereoselec-

tive allylation reaction to synthesize homoallylic primary amines (Scheme

21) In addition several useful methods for asymmetric allylboration of

imines25b 51

using allylboronates can also be found in literature

Scheme 21 Synthesis of homoallylic amine using multicomponent method

50

Allylboration of acylhydrazones have also proven to be a very useful

reaction for the synthesis of homoallylic amine derivatives However the

allylation of acylhydrazones by allylboronates requires the application of

metal catalysts52

An indium-catalyzed reaction for the allylation of N-

acylhydrazone was reported by Kobayashi and co-workers (Scheme 22)52a

It

has been proposed that indium undergoes a transmetallation with allyl-Bpin

to form an active allyl-indium species which then added to the hydrazone

10

Scheme 22 Indium-catalyzed allylation of acylhydrazone

52a

We have developed a stereoselective method for allylation of imines and

acylhydrazones using allylboronic acids These results are summarized in

Chapter 6

11

2 Pd-catalyzed stereoselective allylic CminusH

trifluoroacetoxylation (Paper I)

As mentioned in the introduction transition metal-catalyzed CminusH bond activation methods have attracted increasing interest in organic synthesis

53

Using these methods multistep synthesis for prefunctionalization of the or-ganic substrates is not necessary In addition the waste production of the reaction can be reduced as the new functional group can be installed by re-placement of hydrogen

54 Palladium-catalyzed allylic CminusH bond activation is

one of the oldest and most versatile CminusH functionalization method (Section 11)

55 In this reaction (as in CminusH activation based processes in general) the

greatest challenge is the control of the regio- and stereoselectivity of the process

Stereodefined allylic acetates are very important precursors for regio- and stereoselective palladium-catalyzed allylic substitution reactions

56 Although

many regioselective allylic CminusH functionalization methods have been re-ported there are few reports on stereoselective allylic CminusH acetoxylation

7a

Most of these studies are intramolecular CminusH acyloxylation reactions For example a stereoselective allylic CminusH acetoxylation method has been re-ported by White and co-workers (Scheme 23) Intramolecular selectivity control allowed macrocyclization

57 and straightforward synthesis of anti-14-

dioxan-2-ones58

from simple olefins using Pd(II)sulfoxide catalysis Baumlck-vall and co-workers

59 have also developed several methods for the synthesis

of allylacetoxy compounds based on palladium-catalyzed intramolecular oxidative carbocyclization

Scheme 23 Stereoselective intramolecular CminusH oxidation reported by White and

co-workers58

12

21 Development of selective intermolecular allylic CminusH trifluoroacetoxylation

As our group previously developed a useful allylic CminusH acetoxylation

method based on using PhI(OAc)2 (2a) (see Section 11) as oxidant and ace-

tate source we envisioned that PhI(OCOCF3)2 (2b) can also be used in this

type of reaction to introduce a trifluoroacetate group at the allylic position of

alkenes Allylic trifluoroacetates are more reactive than allylic acetates in

transition metal-catalyzed substitutions60

and therefore an easy access to

these compounds is desirable As far as we know selective allylic CminusH tri-

fluoroacetoxylation has not been reported in the literature

In the early stage of development and optimization we employed car-

boxylated alkene 6a as our model substrate as it gave a high yield and ex-

hibited high selectivity in the Pd-catalyzed CminusH acetoxylation with 2a11b

However PhI(OCOCF3)2 (2b) is most likely a stronger oxidant than

PhI(OAc)2 (2a) and therefore we could not use oxidation sensitive solvents

such as THF or DMSO In addition the conjugated acid of the trifluoroace-

tate ion (the nucleophile) is a strong acid and therefore trifluoroacetic acid

could not be used as the solvent either After short optimization we have

found that dimethyl carbonate (DMC) is an excellent solvent for all reaction

components and it is not oxidized by PIFA We have found that the isolated

yields are higher when LiOCOCF3 is used as additive Under these condi-

tions the reaction could be performed with various functionalized alkenes

(Table 1)

13

Table 1 Pd-catalyzed allylic CminusH trifluoroacetoxylation of acyclic olefinsa

Both Pd(OAc)2 (5b) and Pd(OCOCF3)2 (5c) were equally efficient as cat-

alyst in the reaction So we decided to use 5b in the present synthetic method

as it is less expensive than 5c Not only terminal (6a) but internal alkenes

6b-c could also be used for trifluoroacetoxylation with high selectivity Oth-

er alkenes with electron withdrawing substituents such as 6d-e could also be

smoothly trifluoroacetoxylated Substrates without electron-withdrawing

groups gave intractable mixtures of trifluoroacetoxylated products For com-

pounds with long alkyl chain oxidation of the double bond occurred while in

the case of electron donating substituents mainly oxidation of the double

bond occurred together with other processes

14

Table 2 Stereoselective allylic CminusH trifluoroacetoxylation of cyclic alkenesa

Not only acyclic alkenes but cyclic alkenes could also be employed for

the trifluoroacetoxylation reaction Monosubstituted cyclic alkenes reacted

with a remarkably high selectivity (Table 2) The reaction conditions were

very similar to the trifluoroacetoxylation of acyclic substrates (Table 1) but

in order to get this high stereoselectivity the reactions had to be conducted

at 0 degC This is below the freezing point of DMC therefore the reaction me-

dium was diluted with DCM to avoid freezing of the reaction mixture The

yields with LiOCOCF3 were as high as in its absence therefore we did not

use this additive in the trifluoroacetoxylation of cyclic substrates

Considering the number of possible regio- and stereoisomers a mixture

of six allylic trifluoroacetate products could be expected Yet in most cases

we obtained a single diastereomer with very high regioselectivity (Table 2

entries 1-2 and 4-5) The major regioisomer in all cases was the 14-

substituted product (7f-j) with anti diastereoselectivity and the minor prod-

uct is the regioisomer of the same diastereomer The stereochemistry of the

major isomers was assigned based on NOE experiments

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

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3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

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5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

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45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

8

Scheme 17 Tin-catalyzed asymmetric allylboration of aldehyde

42a

Asymmetric allylation of ketones was reported using chiral allylboronate

derived from BINOL compounds Chong and co-workers described the al-

lylation of ketones using 33-(CF3)2-BINOL boronate 3a (Scheme 18)43

The

reaction gave homoallylic alcohol product with a high level of enantioselec-

tivity

Scheme 18 Asymmetric allylation of ketone using BINOL-boronate

43

Catalytic methods have also been described to control both diastereo- and

enantioselectivity in the allylboration of ketones44

The first catalytic

enantioselective allylboration of ketones was developed by Shibasaki and

co-workers45

Broslashnsted acid such as BINOL derivatives44 46

was found to be

very efficient in the asymmetric allylboration reactions Schaus and

co-workers44

reported a method for asymmetric allylation of ketones using

isopropoxyboronate and catalytic amounts of Br2-BINOL 4a (Scheme 19)

Scheme 19 Catalytic asymmetric allylboration of ketone using Br2-BINOL

44a

These authors proposed a Zimmerman-Traxler type transition state to

rationalize the enantioselectivity in this reaction It has been also pointed out

that the substituent in BINOL (eg Br or CF3) has an important role for the

enantioselectivity of these reactions

Catalytic synthesis of homoallylic alcohols containing adjacent quater-

nary stereocenters has been a great challenge in synthetic organic chemistry

A new synthetic method for such reaction is presented in Section 52

9

133 Stereoselective allylation of imines

Homoallylic amine motifs occur in many natural products and biological-

ly relevant compounds47

One of the most common strategies for homoallylic

amine synthesis is the addition of allyl-metal reagents to imines48

The use of

allylboronate compounds for these reactions has emerged as an important

synthetic approach47

Allylboronates have a low toxicity high functional

group tolerance and the allylation of imines occurs with a high level of

selectivity

Stereoselective allylation of aldimines can be performed by

allylboronates in the presence of Lewis acid catalysts Batey and

co-workers49

reported the allylboration of N-toluenesulfonylimines using

crotyltrifluroboronate and BF3OEt2 (Scheme 20) The allylation was

proposed to proceed via the allyl-BF2 species which is generated from

allyl-BF3K

Scheme 20 Stereoselective allylation of imine by allyltrifluoroborate

49

Kobayashi and co-workers50

reported a three-component diastereoselec-

tive allylation reaction to synthesize homoallylic primary amines (Scheme

21) In addition several useful methods for asymmetric allylboration of

imines25b 51

using allylboronates can also be found in literature

Scheme 21 Synthesis of homoallylic amine using multicomponent method

50

Allylboration of acylhydrazones have also proven to be a very useful

reaction for the synthesis of homoallylic amine derivatives However the

allylation of acylhydrazones by allylboronates requires the application of

metal catalysts52

An indium-catalyzed reaction for the allylation of N-

acylhydrazone was reported by Kobayashi and co-workers (Scheme 22)52a

It

has been proposed that indium undergoes a transmetallation with allyl-Bpin

to form an active allyl-indium species which then added to the hydrazone

10

Scheme 22 Indium-catalyzed allylation of acylhydrazone

52a

We have developed a stereoselective method for allylation of imines and

acylhydrazones using allylboronic acids These results are summarized in

Chapter 6

11

2 Pd-catalyzed stereoselective allylic CminusH

trifluoroacetoxylation (Paper I)

As mentioned in the introduction transition metal-catalyzed CminusH bond activation methods have attracted increasing interest in organic synthesis

53

Using these methods multistep synthesis for prefunctionalization of the or-ganic substrates is not necessary In addition the waste production of the reaction can be reduced as the new functional group can be installed by re-placement of hydrogen

54 Palladium-catalyzed allylic CminusH bond activation is

one of the oldest and most versatile CminusH functionalization method (Section 11)

55 In this reaction (as in CminusH activation based processes in general) the

greatest challenge is the control of the regio- and stereoselectivity of the process

Stereodefined allylic acetates are very important precursors for regio- and stereoselective palladium-catalyzed allylic substitution reactions

56 Although

many regioselective allylic CminusH functionalization methods have been re-ported there are few reports on stereoselective allylic CminusH acetoxylation

7a

Most of these studies are intramolecular CminusH acyloxylation reactions For example a stereoselective allylic CminusH acetoxylation method has been re-ported by White and co-workers (Scheme 23) Intramolecular selectivity control allowed macrocyclization

57 and straightforward synthesis of anti-14-

dioxan-2-ones58

from simple olefins using Pd(II)sulfoxide catalysis Baumlck-vall and co-workers

59 have also developed several methods for the synthesis

of allylacetoxy compounds based on palladium-catalyzed intramolecular oxidative carbocyclization

Scheme 23 Stereoselective intramolecular CminusH oxidation reported by White and

co-workers58

12

21 Development of selective intermolecular allylic CminusH trifluoroacetoxylation

As our group previously developed a useful allylic CminusH acetoxylation

method based on using PhI(OAc)2 (2a) (see Section 11) as oxidant and ace-

tate source we envisioned that PhI(OCOCF3)2 (2b) can also be used in this

type of reaction to introduce a trifluoroacetate group at the allylic position of

alkenes Allylic trifluoroacetates are more reactive than allylic acetates in

transition metal-catalyzed substitutions60

and therefore an easy access to

these compounds is desirable As far as we know selective allylic CminusH tri-

fluoroacetoxylation has not been reported in the literature

In the early stage of development and optimization we employed car-

boxylated alkene 6a as our model substrate as it gave a high yield and ex-

hibited high selectivity in the Pd-catalyzed CminusH acetoxylation with 2a11b

However PhI(OCOCF3)2 (2b) is most likely a stronger oxidant than

PhI(OAc)2 (2a) and therefore we could not use oxidation sensitive solvents

such as THF or DMSO In addition the conjugated acid of the trifluoroace-

tate ion (the nucleophile) is a strong acid and therefore trifluoroacetic acid

could not be used as the solvent either After short optimization we have

found that dimethyl carbonate (DMC) is an excellent solvent for all reaction

components and it is not oxidized by PIFA We have found that the isolated

yields are higher when LiOCOCF3 is used as additive Under these condi-

tions the reaction could be performed with various functionalized alkenes

(Table 1)

13

Table 1 Pd-catalyzed allylic CminusH trifluoroacetoxylation of acyclic olefinsa

Both Pd(OAc)2 (5b) and Pd(OCOCF3)2 (5c) were equally efficient as cat-

alyst in the reaction So we decided to use 5b in the present synthetic method

as it is less expensive than 5c Not only terminal (6a) but internal alkenes

6b-c could also be used for trifluoroacetoxylation with high selectivity Oth-

er alkenes with electron withdrawing substituents such as 6d-e could also be

smoothly trifluoroacetoxylated Substrates without electron-withdrawing

groups gave intractable mixtures of trifluoroacetoxylated products For com-

pounds with long alkyl chain oxidation of the double bond occurred while in

the case of electron donating substituents mainly oxidation of the double

bond occurred together with other processes

14

Table 2 Stereoselective allylic CminusH trifluoroacetoxylation of cyclic alkenesa

Not only acyclic alkenes but cyclic alkenes could also be employed for

the trifluoroacetoxylation reaction Monosubstituted cyclic alkenes reacted

with a remarkably high selectivity (Table 2) The reaction conditions were

very similar to the trifluoroacetoxylation of acyclic substrates (Table 1) but

in order to get this high stereoselectivity the reactions had to be conducted

at 0 degC This is below the freezing point of DMC therefore the reaction me-

dium was diluted with DCM to avoid freezing of the reaction mixture The

yields with LiOCOCF3 were as high as in its absence therefore we did not

use this additive in the trifluoroacetoxylation of cyclic substrates

Considering the number of possible regio- and stereoisomers a mixture

of six allylic trifluoroacetate products could be expected Yet in most cases

we obtained a single diastereomer with very high regioselectivity (Table 2

entries 1-2 and 4-5) The major regioisomer in all cases was the 14-

substituted product (7f-j) with anti diastereoselectivity and the minor prod-

uct is the regioisomer of the same diastereomer The stereochemistry of the

major isomers was assigned based on NOE experiments

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

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3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

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16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

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20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

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1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

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1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

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45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

9

133 Stereoselective allylation of imines

Homoallylic amine motifs occur in many natural products and biological-

ly relevant compounds47

One of the most common strategies for homoallylic

amine synthesis is the addition of allyl-metal reagents to imines48

The use of

allylboronate compounds for these reactions has emerged as an important

synthetic approach47

Allylboronates have a low toxicity high functional

group tolerance and the allylation of imines occurs with a high level of

selectivity

Stereoselective allylation of aldimines can be performed by

allylboronates in the presence of Lewis acid catalysts Batey and

co-workers49

reported the allylboration of N-toluenesulfonylimines using

crotyltrifluroboronate and BF3OEt2 (Scheme 20) The allylation was

proposed to proceed via the allyl-BF2 species which is generated from

allyl-BF3K

Scheme 20 Stereoselective allylation of imine by allyltrifluoroborate

49

Kobayashi and co-workers50

reported a three-component diastereoselec-

tive allylation reaction to synthesize homoallylic primary amines (Scheme

21) In addition several useful methods for asymmetric allylboration of

imines25b 51

using allylboronates can also be found in literature

Scheme 21 Synthesis of homoallylic amine using multicomponent method

50

Allylboration of acylhydrazones have also proven to be a very useful

reaction for the synthesis of homoallylic amine derivatives However the

allylation of acylhydrazones by allylboronates requires the application of

metal catalysts52

An indium-catalyzed reaction for the allylation of N-

acylhydrazone was reported by Kobayashi and co-workers (Scheme 22)52a

It

has been proposed that indium undergoes a transmetallation with allyl-Bpin

to form an active allyl-indium species which then added to the hydrazone

10

Scheme 22 Indium-catalyzed allylation of acylhydrazone

52a

We have developed a stereoselective method for allylation of imines and

acylhydrazones using allylboronic acids These results are summarized in

Chapter 6

11

2 Pd-catalyzed stereoselective allylic CminusH

trifluoroacetoxylation (Paper I)

As mentioned in the introduction transition metal-catalyzed CminusH bond activation methods have attracted increasing interest in organic synthesis

53

Using these methods multistep synthesis for prefunctionalization of the or-ganic substrates is not necessary In addition the waste production of the reaction can be reduced as the new functional group can be installed by re-placement of hydrogen

54 Palladium-catalyzed allylic CminusH bond activation is

one of the oldest and most versatile CminusH functionalization method (Section 11)

55 In this reaction (as in CminusH activation based processes in general) the

greatest challenge is the control of the regio- and stereoselectivity of the process

Stereodefined allylic acetates are very important precursors for regio- and stereoselective palladium-catalyzed allylic substitution reactions

56 Although

many regioselective allylic CminusH functionalization methods have been re-ported there are few reports on stereoselective allylic CminusH acetoxylation

7a

Most of these studies are intramolecular CminusH acyloxylation reactions For example a stereoselective allylic CminusH acetoxylation method has been re-ported by White and co-workers (Scheme 23) Intramolecular selectivity control allowed macrocyclization

57 and straightforward synthesis of anti-14-

dioxan-2-ones58

from simple olefins using Pd(II)sulfoxide catalysis Baumlck-vall and co-workers

59 have also developed several methods for the synthesis

of allylacetoxy compounds based on palladium-catalyzed intramolecular oxidative carbocyclization

Scheme 23 Stereoselective intramolecular CminusH oxidation reported by White and

co-workers58

12

21 Development of selective intermolecular allylic CminusH trifluoroacetoxylation

As our group previously developed a useful allylic CminusH acetoxylation

method based on using PhI(OAc)2 (2a) (see Section 11) as oxidant and ace-

tate source we envisioned that PhI(OCOCF3)2 (2b) can also be used in this

type of reaction to introduce a trifluoroacetate group at the allylic position of

alkenes Allylic trifluoroacetates are more reactive than allylic acetates in

transition metal-catalyzed substitutions60

and therefore an easy access to

these compounds is desirable As far as we know selective allylic CminusH tri-

fluoroacetoxylation has not been reported in the literature

In the early stage of development and optimization we employed car-

boxylated alkene 6a as our model substrate as it gave a high yield and ex-

hibited high selectivity in the Pd-catalyzed CminusH acetoxylation with 2a11b

However PhI(OCOCF3)2 (2b) is most likely a stronger oxidant than

PhI(OAc)2 (2a) and therefore we could not use oxidation sensitive solvents

such as THF or DMSO In addition the conjugated acid of the trifluoroace-

tate ion (the nucleophile) is a strong acid and therefore trifluoroacetic acid

could not be used as the solvent either After short optimization we have

found that dimethyl carbonate (DMC) is an excellent solvent for all reaction

components and it is not oxidized by PIFA We have found that the isolated

yields are higher when LiOCOCF3 is used as additive Under these condi-

tions the reaction could be performed with various functionalized alkenes

(Table 1)

13

Table 1 Pd-catalyzed allylic CminusH trifluoroacetoxylation of acyclic olefinsa

Both Pd(OAc)2 (5b) and Pd(OCOCF3)2 (5c) were equally efficient as cat-

alyst in the reaction So we decided to use 5b in the present synthetic method

as it is less expensive than 5c Not only terminal (6a) but internal alkenes

6b-c could also be used for trifluoroacetoxylation with high selectivity Oth-

er alkenes with electron withdrawing substituents such as 6d-e could also be

smoothly trifluoroacetoxylated Substrates without electron-withdrawing

groups gave intractable mixtures of trifluoroacetoxylated products For com-

pounds with long alkyl chain oxidation of the double bond occurred while in

the case of electron donating substituents mainly oxidation of the double

bond occurred together with other processes

14

Table 2 Stereoselective allylic CminusH trifluoroacetoxylation of cyclic alkenesa

Not only acyclic alkenes but cyclic alkenes could also be employed for

the trifluoroacetoxylation reaction Monosubstituted cyclic alkenes reacted

with a remarkably high selectivity (Table 2) The reaction conditions were

very similar to the trifluoroacetoxylation of acyclic substrates (Table 1) but

in order to get this high stereoselectivity the reactions had to be conducted

at 0 degC This is below the freezing point of DMC therefore the reaction me-

dium was diluted with DCM to avoid freezing of the reaction mixture The

yields with LiOCOCF3 were as high as in its absence therefore we did not

use this additive in the trifluoroacetoxylation of cyclic substrates

Considering the number of possible regio- and stereoisomers a mixture

of six allylic trifluoroacetate products could be expected Yet in most cases

we obtained a single diastereomer with very high regioselectivity (Table 2

entries 1-2 and 4-5) The major regioisomer in all cases was the 14-

substituted product (7f-j) with anti diastereoselectivity and the minor prod-

uct is the regioisomer of the same diastereomer The stereochemistry of the

major isomers was assigned based on NOE experiments

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

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3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

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78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

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39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

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45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

10

Scheme 22 Indium-catalyzed allylation of acylhydrazone

52a

We have developed a stereoselective method for allylation of imines and

acylhydrazones using allylboronic acids These results are summarized in

Chapter 6

11

2 Pd-catalyzed stereoselective allylic CminusH

trifluoroacetoxylation (Paper I)

As mentioned in the introduction transition metal-catalyzed CminusH bond activation methods have attracted increasing interest in organic synthesis

53

Using these methods multistep synthesis for prefunctionalization of the or-ganic substrates is not necessary In addition the waste production of the reaction can be reduced as the new functional group can be installed by re-placement of hydrogen

54 Palladium-catalyzed allylic CminusH bond activation is

one of the oldest and most versatile CminusH functionalization method (Section 11)

55 In this reaction (as in CminusH activation based processes in general) the

greatest challenge is the control of the regio- and stereoselectivity of the process

Stereodefined allylic acetates are very important precursors for regio- and stereoselective palladium-catalyzed allylic substitution reactions

56 Although

many regioselective allylic CminusH functionalization methods have been re-ported there are few reports on stereoselective allylic CminusH acetoxylation

7a

Most of these studies are intramolecular CminusH acyloxylation reactions For example a stereoselective allylic CminusH acetoxylation method has been re-ported by White and co-workers (Scheme 23) Intramolecular selectivity control allowed macrocyclization

57 and straightforward synthesis of anti-14-

dioxan-2-ones58

from simple olefins using Pd(II)sulfoxide catalysis Baumlck-vall and co-workers

59 have also developed several methods for the synthesis

of allylacetoxy compounds based on palladium-catalyzed intramolecular oxidative carbocyclization

Scheme 23 Stereoselective intramolecular CminusH oxidation reported by White and

co-workers58

12

21 Development of selective intermolecular allylic CminusH trifluoroacetoxylation

As our group previously developed a useful allylic CminusH acetoxylation

method based on using PhI(OAc)2 (2a) (see Section 11) as oxidant and ace-

tate source we envisioned that PhI(OCOCF3)2 (2b) can also be used in this

type of reaction to introduce a trifluoroacetate group at the allylic position of

alkenes Allylic trifluoroacetates are more reactive than allylic acetates in

transition metal-catalyzed substitutions60

and therefore an easy access to

these compounds is desirable As far as we know selective allylic CminusH tri-

fluoroacetoxylation has not been reported in the literature

In the early stage of development and optimization we employed car-

boxylated alkene 6a as our model substrate as it gave a high yield and ex-

hibited high selectivity in the Pd-catalyzed CminusH acetoxylation with 2a11b

However PhI(OCOCF3)2 (2b) is most likely a stronger oxidant than

PhI(OAc)2 (2a) and therefore we could not use oxidation sensitive solvents

such as THF or DMSO In addition the conjugated acid of the trifluoroace-

tate ion (the nucleophile) is a strong acid and therefore trifluoroacetic acid

could not be used as the solvent either After short optimization we have

found that dimethyl carbonate (DMC) is an excellent solvent for all reaction

components and it is not oxidized by PIFA We have found that the isolated

yields are higher when LiOCOCF3 is used as additive Under these condi-

tions the reaction could be performed with various functionalized alkenes

(Table 1)

13

Table 1 Pd-catalyzed allylic CminusH trifluoroacetoxylation of acyclic olefinsa

Both Pd(OAc)2 (5b) and Pd(OCOCF3)2 (5c) were equally efficient as cat-

alyst in the reaction So we decided to use 5b in the present synthetic method

as it is less expensive than 5c Not only terminal (6a) but internal alkenes

6b-c could also be used for trifluoroacetoxylation with high selectivity Oth-

er alkenes with electron withdrawing substituents such as 6d-e could also be

smoothly trifluoroacetoxylated Substrates without electron-withdrawing

groups gave intractable mixtures of trifluoroacetoxylated products For com-

pounds with long alkyl chain oxidation of the double bond occurred while in

the case of electron donating substituents mainly oxidation of the double

bond occurred together with other processes

14

Table 2 Stereoselective allylic CminusH trifluoroacetoxylation of cyclic alkenesa

Not only acyclic alkenes but cyclic alkenes could also be employed for

the trifluoroacetoxylation reaction Monosubstituted cyclic alkenes reacted

with a remarkably high selectivity (Table 2) The reaction conditions were

very similar to the trifluoroacetoxylation of acyclic substrates (Table 1) but

in order to get this high stereoselectivity the reactions had to be conducted

at 0 degC This is below the freezing point of DMC therefore the reaction me-

dium was diluted with DCM to avoid freezing of the reaction mixture The

yields with LiOCOCF3 were as high as in its absence therefore we did not

use this additive in the trifluoroacetoxylation of cyclic substrates

Considering the number of possible regio- and stereoisomers a mixture

of six allylic trifluoroacetate products could be expected Yet in most cases

we obtained a single diastereomer with very high regioselectivity (Table 2

entries 1-2 and 4-5) The major regioisomer in all cases was the 14-

substituted product (7f-j) with anti diastereoselectivity and the minor prod-

uct is the regioisomer of the same diastereomer The stereochemistry of the

major isomers was assigned based on NOE experiments

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

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11

2 Pd-catalyzed stereoselective allylic CminusH

trifluoroacetoxylation (Paper I)

As mentioned in the introduction transition metal-catalyzed CminusH bond activation methods have attracted increasing interest in organic synthesis

53

Using these methods multistep synthesis for prefunctionalization of the or-ganic substrates is not necessary In addition the waste production of the reaction can be reduced as the new functional group can be installed by re-placement of hydrogen

54 Palladium-catalyzed allylic CminusH bond activation is

one of the oldest and most versatile CminusH functionalization method (Section 11)

55 In this reaction (as in CminusH activation based processes in general) the

greatest challenge is the control of the regio- and stereoselectivity of the process

Stereodefined allylic acetates are very important precursors for regio- and stereoselective palladium-catalyzed allylic substitution reactions

56 Although

many regioselective allylic CminusH functionalization methods have been re-ported there are few reports on stereoselective allylic CminusH acetoxylation

7a

Most of these studies are intramolecular CminusH acyloxylation reactions For example a stereoselective allylic CminusH acetoxylation method has been re-ported by White and co-workers (Scheme 23) Intramolecular selectivity control allowed macrocyclization

57 and straightforward synthesis of anti-14-

dioxan-2-ones58

from simple olefins using Pd(II)sulfoxide catalysis Baumlck-vall and co-workers

59 have also developed several methods for the synthesis

of allylacetoxy compounds based on palladium-catalyzed intramolecular oxidative carbocyclization

Scheme 23 Stereoselective intramolecular CminusH oxidation reported by White and

co-workers58

12

21 Development of selective intermolecular allylic CminusH trifluoroacetoxylation

As our group previously developed a useful allylic CminusH acetoxylation

method based on using PhI(OAc)2 (2a) (see Section 11) as oxidant and ace-

tate source we envisioned that PhI(OCOCF3)2 (2b) can also be used in this

type of reaction to introduce a trifluoroacetate group at the allylic position of

alkenes Allylic trifluoroacetates are more reactive than allylic acetates in

transition metal-catalyzed substitutions60

and therefore an easy access to

these compounds is desirable As far as we know selective allylic CminusH tri-

fluoroacetoxylation has not been reported in the literature

In the early stage of development and optimization we employed car-

boxylated alkene 6a as our model substrate as it gave a high yield and ex-

hibited high selectivity in the Pd-catalyzed CminusH acetoxylation with 2a11b

However PhI(OCOCF3)2 (2b) is most likely a stronger oxidant than

PhI(OAc)2 (2a) and therefore we could not use oxidation sensitive solvents

such as THF or DMSO In addition the conjugated acid of the trifluoroace-

tate ion (the nucleophile) is a strong acid and therefore trifluoroacetic acid

could not be used as the solvent either After short optimization we have

found that dimethyl carbonate (DMC) is an excellent solvent for all reaction

components and it is not oxidized by PIFA We have found that the isolated

yields are higher when LiOCOCF3 is used as additive Under these condi-

tions the reaction could be performed with various functionalized alkenes

(Table 1)

13

Table 1 Pd-catalyzed allylic CminusH trifluoroacetoxylation of acyclic olefinsa

Both Pd(OAc)2 (5b) and Pd(OCOCF3)2 (5c) were equally efficient as cat-

alyst in the reaction So we decided to use 5b in the present synthetic method

as it is less expensive than 5c Not only terminal (6a) but internal alkenes

6b-c could also be used for trifluoroacetoxylation with high selectivity Oth-

er alkenes with electron withdrawing substituents such as 6d-e could also be

smoothly trifluoroacetoxylated Substrates without electron-withdrawing

groups gave intractable mixtures of trifluoroacetoxylated products For com-

pounds with long alkyl chain oxidation of the double bond occurred while in

the case of electron donating substituents mainly oxidation of the double

bond occurred together with other processes

14

Table 2 Stereoselective allylic CminusH trifluoroacetoxylation of cyclic alkenesa

Not only acyclic alkenes but cyclic alkenes could also be employed for

the trifluoroacetoxylation reaction Monosubstituted cyclic alkenes reacted

with a remarkably high selectivity (Table 2) The reaction conditions were

very similar to the trifluoroacetoxylation of acyclic substrates (Table 1) but

in order to get this high stereoselectivity the reactions had to be conducted

at 0 degC This is below the freezing point of DMC therefore the reaction me-

dium was diluted with DCM to avoid freezing of the reaction mixture The

yields with LiOCOCF3 were as high as in its absence therefore we did not

use this additive in the trifluoroacetoxylation of cyclic substrates

Considering the number of possible regio- and stereoisomers a mixture

of six allylic trifluoroacetate products could be expected Yet in most cases

we obtained a single diastereomer with very high regioselectivity (Table 2

entries 1-2 and 4-5) The major regioisomer in all cases was the 14-

substituted product (7f-j) with anti diastereoselectivity and the minor prod-

uct is the regioisomer of the same diastereomer The stereochemistry of the

major isomers was assigned based on NOE experiments

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

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94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

12

21 Development of selective intermolecular allylic CminusH trifluoroacetoxylation

As our group previously developed a useful allylic CminusH acetoxylation

method based on using PhI(OAc)2 (2a) (see Section 11) as oxidant and ace-

tate source we envisioned that PhI(OCOCF3)2 (2b) can also be used in this

type of reaction to introduce a trifluoroacetate group at the allylic position of

alkenes Allylic trifluoroacetates are more reactive than allylic acetates in

transition metal-catalyzed substitutions60

and therefore an easy access to

these compounds is desirable As far as we know selective allylic CminusH tri-

fluoroacetoxylation has not been reported in the literature

In the early stage of development and optimization we employed car-

boxylated alkene 6a as our model substrate as it gave a high yield and ex-

hibited high selectivity in the Pd-catalyzed CminusH acetoxylation with 2a11b

However PhI(OCOCF3)2 (2b) is most likely a stronger oxidant than

PhI(OAc)2 (2a) and therefore we could not use oxidation sensitive solvents

such as THF or DMSO In addition the conjugated acid of the trifluoroace-

tate ion (the nucleophile) is a strong acid and therefore trifluoroacetic acid

could not be used as the solvent either After short optimization we have

found that dimethyl carbonate (DMC) is an excellent solvent for all reaction

components and it is not oxidized by PIFA We have found that the isolated

yields are higher when LiOCOCF3 is used as additive Under these condi-

tions the reaction could be performed with various functionalized alkenes

(Table 1)

13

Table 1 Pd-catalyzed allylic CminusH trifluoroacetoxylation of acyclic olefinsa

Both Pd(OAc)2 (5b) and Pd(OCOCF3)2 (5c) were equally efficient as cat-

alyst in the reaction So we decided to use 5b in the present synthetic method

as it is less expensive than 5c Not only terminal (6a) but internal alkenes

6b-c could also be used for trifluoroacetoxylation with high selectivity Oth-

er alkenes with electron withdrawing substituents such as 6d-e could also be

smoothly trifluoroacetoxylated Substrates without electron-withdrawing

groups gave intractable mixtures of trifluoroacetoxylated products For com-

pounds with long alkyl chain oxidation of the double bond occurred while in

the case of electron donating substituents mainly oxidation of the double

bond occurred together with other processes

14

Table 2 Stereoselective allylic CminusH trifluoroacetoxylation of cyclic alkenesa

Not only acyclic alkenes but cyclic alkenes could also be employed for

the trifluoroacetoxylation reaction Monosubstituted cyclic alkenes reacted

with a remarkably high selectivity (Table 2) The reaction conditions were

very similar to the trifluoroacetoxylation of acyclic substrates (Table 1) but

in order to get this high stereoselectivity the reactions had to be conducted

at 0 degC This is below the freezing point of DMC therefore the reaction me-

dium was diluted with DCM to avoid freezing of the reaction mixture The

yields with LiOCOCF3 were as high as in its absence therefore we did not

use this additive in the trifluoroacetoxylation of cyclic substrates

Considering the number of possible regio- and stereoisomers a mixture

of six allylic trifluoroacetate products could be expected Yet in most cases

we obtained a single diastereomer with very high regioselectivity (Table 2

entries 1-2 and 4-5) The major regioisomer in all cases was the 14-

substituted product (7f-j) with anti diastereoselectivity and the minor prod-

uct is the regioisomer of the same diastereomer The stereochemistry of the

major isomers was assigned based on NOE experiments

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

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J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

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1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

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45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

13

Table 1 Pd-catalyzed allylic CminusH trifluoroacetoxylation of acyclic olefinsa

Both Pd(OAc)2 (5b) and Pd(OCOCF3)2 (5c) were equally efficient as cat-

alyst in the reaction So we decided to use 5b in the present synthetic method

as it is less expensive than 5c Not only terminal (6a) but internal alkenes

6b-c could also be used for trifluoroacetoxylation with high selectivity Oth-

er alkenes with electron withdrawing substituents such as 6d-e could also be

smoothly trifluoroacetoxylated Substrates without electron-withdrawing

groups gave intractable mixtures of trifluoroacetoxylated products For com-

pounds with long alkyl chain oxidation of the double bond occurred while in

the case of electron donating substituents mainly oxidation of the double

bond occurred together with other processes

14

Table 2 Stereoselective allylic CminusH trifluoroacetoxylation of cyclic alkenesa

Not only acyclic alkenes but cyclic alkenes could also be employed for

the trifluoroacetoxylation reaction Monosubstituted cyclic alkenes reacted

with a remarkably high selectivity (Table 2) The reaction conditions were

very similar to the trifluoroacetoxylation of acyclic substrates (Table 1) but

in order to get this high stereoselectivity the reactions had to be conducted

at 0 degC This is below the freezing point of DMC therefore the reaction me-

dium was diluted with DCM to avoid freezing of the reaction mixture The

yields with LiOCOCF3 were as high as in its absence therefore we did not

use this additive in the trifluoroacetoxylation of cyclic substrates

Considering the number of possible regio- and stereoisomers a mixture

of six allylic trifluoroacetate products could be expected Yet in most cases

we obtained a single diastereomer with very high regioselectivity (Table 2

entries 1-2 and 4-5) The major regioisomer in all cases was the 14-

substituted product (7f-j) with anti diastereoselectivity and the minor prod-

uct is the regioisomer of the same diastereomer The stereochemistry of the

major isomers was assigned based on NOE experiments

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

1 The ACS Style Guide 3rd ed Oxford University Press New York 2006

2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

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14

Table 2 Stereoselective allylic CminusH trifluoroacetoxylation of cyclic alkenesa

Not only acyclic alkenes but cyclic alkenes could also be employed for

the trifluoroacetoxylation reaction Monosubstituted cyclic alkenes reacted

with a remarkably high selectivity (Table 2) The reaction conditions were

very similar to the trifluoroacetoxylation of acyclic substrates (Table 1) but

in order to get this high stereoselectivity the reactions had to be conducted

at 0 degC This is below the freezing point of DMC therefore the reaction me-

dium was diluted with DCM to avoid freezing of the reaction mixture The

yields with LiOCOCF3 were as high as in its absence therefore we did not

use this additive in the trifluoroacetoxylation of cyclic substrates

Considering the number of possible regio- and stereoisomers a mixture

of six allylic trifluoroacetate products could be expected Yet in most cases

we obtained a single diastereomer with very high regioselectivity (Table 2

entries 1-2 and 4-5) The major regioisomer in all cases was the 14-

substituted product (7f-j) with anti diastereoselectivity and the minor prod-

uct is the regioisomer of the same diastereomer The stereochemistry of the

major isomers was assigned based on NOE experiments

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

15

The regioselectivity was slightly dependent on the ring size and the ring

substituents Thus the five membered ring substrates such as 6f gave a

higher selectivity than its six-membered ring counterpart 6i Ester- and keto-

substituted substrates were also trifluoroacetoxylated with better regioselec-

tivity than substrates with an amide substituent (cf entries 1 and 3) The

substituent effect of the amide functionality on the selectivity was also re-

ported in other allylic CminusH acyloxylation reactions For example Stambuli

and co-workers61

reported a drop in the regioselectivity of CminusH acetoxyla-

tion reactions in the presence of the amide functionality

The yields varied from fair to good The main side reaction lowering the

yield was the oxidation of the double bond by PIFA Bis-trifluoroacetoxy

compound 7k (Figure 1) was isolated from the reaction of 6i (entry 4)

Figure 1 Compound 7k was isolated from C-H trifluoroacetoxylation reaction of 6i

22 Mechanistic proposal for the allylic CminusH trifluoroacetoxylation

The stereochemical information of the above reactions with cyclic sub-

strates (Table 2) and previous studies of our group12a

with 2a (see Scheme 2)

suggest that the reaction most likely proceeds via (η3-allyl)palladium(IV)

intermediates There are two plausible ways for the formation of an (η3-

allyl)palladium(IV) species 1) formation of an (η3-allyl)palladium(II) moie-

ty which is subsequently oxidized to (η3-allyl)palladium(IV) or 2) direct

oxidation of the Pd(II) catalyst prior to C-H activation and subsequent for-

mation of an (η3-allyl)palladium(IV) intermediate It is well-established that

(η3-allyl)palladium(II) complexes can be formed from alkenes and Pd(II)

precursors62

and therefore we studied the possible formation of such com-

plexes under catalytic conditions Kurosawa and co-workers63

have shown

that allylic chlorides undergo stereoselective syn oxidative addition with

Pd2(dba)3 when non-coordinating solvents (ie benzene) are used Follow-

ing the similar methodology complex (5e) was prepared from product 7j

(Scheme 24)

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

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2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

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8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

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61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

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14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

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16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

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20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

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1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

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1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

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34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

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39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

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45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

16

Scheme 24 Synthesis of Pd(II) intermediate 5e

Palladium complex 5d was stable enough for purification by silica-gel

chromatography After purification the ligand exchange was performed

using AgOCOCF3 which afforded 5e Complex 5e is one possible reaction

intermediate in the catalytic CminusH trifluoroacetoxylation of 6j We hypothe-

sized that if the (η3-allyl)palladium(II) moiety (5e) is the key intermediate in

our reaction then oxidation of 5e with PIFA (2b) would give compound 7j in

a diastereoselective manner Accordingly 5e was treated with 2b for 1 h at 0

degC in DMC In this process 5e was completely consumed resulting in a

complex mixture in which only traces of 7j was observed (Scheme 25) On

the other hand the catalytic reactions proceeded very cleanly at 0 degC There-

fore we conclude that 5e is less likely an intermediate in the catalytic tri-

fluoroacetoxylation with PIFA 2b (Tables 1-2)

Scheme 25 Stoichiometric oxidation of 5e afforded trace of 7j

On the basis of the above findings (Scheme 25) we assume that the initial

step of the catalytic cycle (Figure 2) of the trifluoroacetoxylation reaction is

oxidation of the Pd(II) catalyst by PIFA (2b) to give Pd(IV) complex 5f

Previous studies in the group have demonstrated that Pd(II) pincer complex-

es undergo such type of oxidation with PIFA17a

Coordination of the alkene

to this complex 5f gives 5g which undergoes allylic C-H cleavage which is

possibly aided by one of the OCOCF3 ligands

Considering the stereochemical outcome of the reaction with cyclic sub-

strates (Table 2) the CminusH bond cleavage is supposed to be stereoselective

The cleavage of the CminusH bond (red colored) in 5g leads to allyl-Pd(IV)

complex 5gprime in which the Pd atom and the R group are on different sides of

the six-membered ring Reductive elimination of 5gprime leads to anti-product 7j

Thus the high regio- and stereoselectivity in the Pd-catalyzed allylic CminusH

trifluoroacetoxylation of the monosubstituted cycloalkenes is based on two

selective steps in the catalytic cycle stereoselective formation of 5gprime and

regioselective reductive elimination of 5gprime

17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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65

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17

Figure 2 Suggested catalytic cycle for Pd-catalyzed allylic C-H trifluoroacetoxyla-

tion

23 Conclusions for the allylic CminusH trifluoroacetoxylation

We have developed a new method for the catalytic allylic CminusH trifluoro-

acetoxylation reaction using a palladium catalyst in the presence of an

oxidant PhI(OCOCF3)2 This methodology is applicable for both acyclic

(terminal and internal) and cyclic olefins The reaction proceeds with

remarkably high regio- and stereoselectivity for the cyclic alkenes The

described method is synthetically useful for the synthesis of stereodefined

cyclic allylic trifluoroacetates from mono-substituted cyclic olefins

18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

1 The ACS Style Guide 3rd ed Oxford University Press New York 2006

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18

3 Pd-catalyzed synthesis and isolation of

allylboronic acids (Paper II)

As mentioned above (Section 12) there is a large interest for the devel-

opment of new methods for the synthesis of allylboronates as these com-

pounds are useful allylating reagents for carbonyl compounds Brown and

co-workers13a

pointed out that allylboronic acids are more reactive allylating

agents than traditionally used allylboronic esters such as allyl-Bpin com-

pounds However the poor stability of allylboronic acids under ambient

conditions prevented their isolation and study of their reactivity

31 Development of new synthetic methods for the synthesis and isolation of allylboronic acids

The palladium-catalyzed synthesis of allylboronic acids was first reported

by Szaboacute and co-workers in 200564

It was also shown that allylboronic acids

can be prepared from allyl alcohols and diboronic acid 9a in a palladium-

catalyzed process (Scheme 26)15a

Although allylboronic acid 10 could be

fully characterized on the basis of the 1H NMR spectrum of the crude

reaction mixture their isolation was not possible When the solvent was

removed allylboronic acids underwent rapid decomposition Therefore it

was appealing to develop new reaction conditions for this reaction which

allow isolation of allylboronic acids 10 in pure form

Scheme 26 Synthesis of allyltrifluoroborates via allylboronic acids

15a

Diboronic acid 9a is an air-stable commercially available compound65

Although it was shown that 9a is an excellent boron source in many transi-

tion metal-catalyzed transformations15c 64 66

it was much less used67

than its

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

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3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

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9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

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12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

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16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

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11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

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45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

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83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

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86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

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88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

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94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

19

pinacol analog B2pin2 One of the reasons is that the structure solubility and

handling of 9a are different from B2pin2 In the next section a couple of im-

portant properties of this reagent are summarized

311 Diboronic acid B2(OH)4 as boron source

Commercially available diboronic acid 9a is often contaminated with

traces of basic impurities most probably HNMe268

Even small traces of base

may inhibit the catalyst in the synthesis of allylboronic acids Therefore

commercially available diboronic acid was purified by washing with dioxane

and water69

Unlike B2pin2 diboronic acid 9a is insoluble in most organic

solvents The exceptions are MeOH EtOH and DMSO in which 9a is readi-

ly soluble Diboronic acid 9a is also fairly soluble in water and therefore

the first choice for the reaction medium using 9a as a B(OH)2 source using

these solvents or their mixtures Another important difference compared to

B2pin2 is that 9a exist as a mixture of monomers dimers and trimers

(Scheme 27) For example 9b and 9c were observed along with 9a in the 1H

NMR spectrum of diboronic acid (Figure 3)65 69

Scheme 27 Formation of boronic acid anhydrides under drying

The oligomeric forms 9b-c easily dissociates to the monomeric form 9a in MeOH or water which was used as solvent or co-solvent

20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

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20

Figure 3

1H NMR spectrum (DMSO-d6) of purified compound 9a

312 Synthesis of allylboronic acids and their isolation

Our studies (see below Section 32) have shown that pure solvent-free

allylboronic acid is highly oxygen sensitive Therefore we developed a syn-

thetic method which allows isolation and purification of allylboronic acids

under strictly oxygen free conditions The final purification of the

allylboronic acids were carried out with precipitationcrystallization of the

products under inert conditions

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

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2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

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11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

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14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

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78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

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39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

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45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

21

Table 3 Pd-catalyzed synthesis of allylboronic acidsa

The initial method development was carried out with cinnamyl alcohol 8a

as model substrate (Table 3) First we employed MeOH as solvent and

Pd(MeCN)4(BF4)2 5i as catalyst Catalyst 5i was particularly efficient for

synthesis of the analog allyl-Bpin compounds and in depth mechanistic stud-

ies indicated that this catalyst efficiently catalyzed several key steps of the

borylation (and silylation) of allyl alcohols16

However the reaction was

very fast and exothermic and except the desired product 10a a lot of by-

products such as allyl benzene was also formed Therefore we employed a

less reactive but more selective catalyst H2PdCl4 5h which can be easily

prepared from PdCl2 and aqueous HCl solution69-70

Using 5h allylboronic

22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

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12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

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16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

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20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

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1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

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37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

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40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

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45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

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61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

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67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

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69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

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1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

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80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

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83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

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22

acid 10a was readily formed from 8a and 9a When the reaction was com-

pleted Pd-black was filtered off under inert conditions and then brine was

added Allylboronic acid 10a precipitated as a white solid which was fil-

tered off under inert conditions (under Ar) and the dry compound was stored

and used in glove box The above procedure is readily scalable A four times

scaling using the above described optimized conditions did not change sig-

nificantly the yield (entry 1 Table 3) 1H NMR studies of allylboronic acids

in dry DMSO indicated that these compounds form allylboroxines which are

very oxygen sensitive Characterization of cinnamyl boroxine is given below

in Section 32

With optimal reaction conditions in hand we aimed to explore the syn-

thetic scope of the reaction Of course we still kept the focus on the possibil-

ities of the isolation and purification of the products under inert conditions

For sterically hindered alcohols 8b-c and 8e the reaction was slower than for

cinnamyl alcohol 8a and large amount of protodeborylated byproducts were

formed Changing the reaction medium to DMSOH2O we could reduce the

amount of the byproducts and 10b-c and 10e was isolated in synthetically

useful yields (entries 2-3) The products from acyclic alcohols are formed as

single trans-isomers The exception is 10b with two substituents in one

terminal position of the double bond This compound was obtained as a 51

mixture of E- and Z-products Geraniol (8f) and nerol (8g) could easily be

borylated but 10f and 10g resisted to any attempts for precipitation Howev-

er we have found that pure samples of 10f-g can be isolated by extraction

with chloroform (entries 6 and 7) Interestingly the double bond geometry of

nerol and geraniol was preserved in the products 10f-g providing interesting

substrates for the studies of the stereochemistry of the allylation reactions

(see Section 41) Cyclic boronic acid 10h was also formed readily but it is

highly soluble in water and DMSO and therefore the isolation could only be

carried out with a substantial loss of the product (entry 8)

32 Characterization of allylboroxine

The formation of boroxines from organoboronic acids is well known71

For example arylboronic acids easily form arylboroxines under drying

However in case of arylboronic acids the corresponding boroxines are usu-

ally air-stable71a

Allylboronic acids also form boroxines under dry condi-

tions (Scheme 28) but unlike aryl boroxines allylboroxines are extremely

air-sensitive and can easily be oxidized We found that isolated allylboronic

acids (such as 10a) decompose rapidly under air in solvent-free conditions

23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

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23

Scheme 28 Allylboronic acids form boroxine under drying condition

Boroxines can be observed by 1H NMR spectroscopy in dry solvent The

1H NMR spectrum of cinnamylboronic acid (10a) along with the correspond-

ing boroxine in dry DMSO is shown in Figure 4 A doublet peak at 158 ppm

corresponds the methylene protons (B-CH2) of the boroxine of 10a The ratio

of the boroxine and the water (at 334 ppm) is same (11) since three mole-

cules of water release during the condensation (Scheme 28) When a trace of

water was added the doublet peak (158 ppm) disappeared (Figure 5) This

shows that formation of boroxine (under oxygen free conditions) is an equi-

librium process

Figure 4 Boroxine formation from compound 10a was identified by

1H NMR in dry

DMSO-d6

24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

1 The ACS Style Guide 3rd ed Oxford University Press New York 2006

2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

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24

Figure 5 Disappearance of boroxine after addition of water

Allylboronic acids were stored and handled in a glove box Cinnamyl bo-

ronic acid 10a could be kept without notable decomposition in a glove box

for a couple weeks at room temperature The boroxine formation does not

affect the thermal stability of the allylboronic acids For example heating of

10c (Table 3) in dry THF under Ar at 70 degC for 18 h did not lead to boro-

tropic rearrangement

33 Proposed mechanism for the allylic CminusOH borylation

Based on the above and previous results of the Szaboacute group15a 15d 72

on

the palladium catalyzed borylation and silylation of allylic alcohols a plau-

sible catalytic cycle is presented in Figure 6 Recent mechanistic studies of

the Szaboacute group16

have shown that in the analogous silylation reaction with

hexamethyldisilane (SiMe3)2 the initial step of the reaction involves reduc-

tion of Pd(II) pro-catalyst to Pd(0) We suggest that the same happens in the

presented borylation reaction as well Complex 5h is reduced by 9a to Pd(0)

catalyst 5j Subsequently 5j undergoes oxidative addition with the protonat-

ed allylic alcohol (8aprime) to give allyl-Pd complex 5k Recent in depth mecha-

nistic studies16

showed that coordination of Lewis acids to the OH group

facilitates the C-O bond cleavage Probably Broslashnsted acids (such as HCl p-

toluene sulfonic acid etc) have the same effect Allyl-Pd complexes such as

5k is known to undergo transmetallation with B2pin216

Therefore we sug-

gest that 5k undergoes transmetallation with 9a to form 5l and subsequent

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

1 The ACS Style Guide 3rd ed Oxford University Press New York 2006

2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

25

reductive elimination from 5l gives allylboronic acid 10a and regenerate the

catalyst 5j

Figure 6 Proposed catalytic cycle for Pd-catalyzed allylic C-OH borylation

34 Conclusions for the allylic CminusOH borylation

Allylboronic acids can be prepared by Pd-catalyzed allylic substitution of

allylic alcohols using diboronic acid as the boron source The resulting al-

lylboronic acids can form boroxines which are very oxygen sensitive

Therefore the isolation of allylboronic acids was carried out under strictly

oxygen free conditions The method for purification and isolation is precipi-

tation by waterbrine under Ar atmosphere The allylboronic acids can be

stored and handled in a glove box

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

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3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

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8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

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61

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12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

26

4 Allylboration of carbonyl compounds using

allylboronic acids (Paper II-III)

Stereoselective synthesis of organic molecules with contiguous stere-

ocenters is of greatest interest in organic synthesis As mentioned in Section

13 allylboration of carbonyl compounds is particularly suitable method to

achieve this goal

41 Allylation of ketones by allylboronic acids

The uncatalyzed reactions of allylboronates such as allyl-Bpin deriva-

tives with carbonyl compounds mostly involve aldehydes as substrates

However allylboronic esters like allyl-Bpin are usually unreactive towards

ketones Hoffman and co-workers73

demonstrated that very harsh conditions

are required for allylboration of acetophenone In addition under these harsh

conditions (8 Kbar pressure) the allylation is practically unselective and can

afford four diasteromeric alcohols (Scheme 29) In all selective allylboration

reactions Lewis-acid or other catalysts were used to activate the allylboronic

esters toward reactions with ketones36b 44a 45

Scheme 29 Addition of allylboronate to acetophenone reported by Hoffmann and

co-workers73

We have found that allylboronic acids (10) readily react with various ke-

tones (11) in the absence of any additives affording homoallylic alcohols

(Scheme 30) The reactions can be performed under mild conditions at room

temperature in dry solvents (typically THF) under Ar (Table 4) Addition of

cinnamylboronic acid (10a) to acetophenone (11a) in THF occurred smooth-

ly at room temperature The reaction was accomplished within 24 h and af-

forded a single diastereoisomer of homoallylic alcohol 12a The addition of

compound 10a to the ketone 11b was very slow at room temperature and

required elevated temperature 60 oC (entry 2) This is probably because of

steric bulkiness in the compound 11b However the diastereoselectivity of

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

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78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

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40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

27

the allylation of 11b was very high and the compound 12b was isolated as a

single diastereoisomer A very fast reaction was observed when acyl cya-

nide 11c was treated with boronic acid 10a (entry 3) As far as we know

only one literature example74

is reported for the preparation of a homoallyl

cyanohydrin However synthesis of stereodefined quaternary cyanohydrins

(12c) by allylation of acyl cyanides was not reported before

Scheme 30 General scheme for the allylation of ketones using allylboronic acids

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

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1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

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34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

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45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

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93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

28

Table 4 Allylation of carbonyl compounds with allylboronic acidsa

Alkynyl ketone (ynone) 11d was reacted with 10d to give stereodefined

15-enyne 12d (entry 4) To the best of our knowledge the presented reac-

tion (entry 4) is the first example for one step synthesis of diastereoselective

15-enynes with adjacent quaternary and tertiary stereocenters29a

Derivatives

of 15-enynes are important substrates for the preparation of four membered

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

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3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

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5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

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40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

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45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

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91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

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93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

29

rings by ring closing metathesis75

We have also found that α-halo ketone

11e reacts with 10a with excellent regio- and stereoselectivity (entry 5) The

reaction proceeded with a clean anti stereoselectivity and the stereochemis-

try of the compound 12e was confirmed by X-ray diffraction method (Figure

7) Knochel and co-workers76

have reported the allylation of α-bromo ke-

tones with cinnamyl zinc derivatives However they proposed that under the

basic conditions of this reaction the bromohydrin products underwent spon-

taneous cyclization to give epoxides even at low temperature (Scheme 31)

Scheme 31 Addition of allylzinc to α-bromo ketone reported by Knochel and co-

workers

In contrary our method provides α-halo hydrin 12e (entry 5) as a single

diastereomer Ethyl pyruvate 11f could also be allylated in very high selec-

tivity (entry 6) As expected the keto group could be selectively functional-

ized in the presence of the ester group The product 12f was obtained as a

single diastereoisomer Pyruvic ester analogue 11g also reacted with 10a

affording single diastereoisomer 12g Interesting results were observed when

geranyl 10f and neryl 10g boronic acids were reacted with acetophenone

derivative 11h (entries 8-9) Compound 10f and 10g were added to ketone

11h at room temperature to give the epimeric products 12h and 12i respec-

tively In products 12h-i two adjacent quaternary stereocenters were formed

Construction of contiguous quaternary stereocenters is one of the most chal-

lenging tasks in synthetic organic chemistry77

Figure 7 X-ray structure for the compound 12e

Surprisingly phenylglyoxylic acid 11i (Table 5) which is structurally

very close to 11g reacted with 10a and afforded poor stereoselectivity (dr

11) under our standard conditions in THF After optimization we found that

the allylation reaction of 11i is highly selective and very fast in MeOH (in-

stead of THF) This was a surprising finding as the allylation reactions with

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

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34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

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91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

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94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

30

other ketones in particularly with acetophenone and its derivatives were

strongly retarded or inhibited in the presence of protic solvents such as

MeOH or water Due to this fact we could not use one-pot conditions for the

generation of allylboronates for allylation of ketones69

Since we found that

α-keto acid (eg 11i) reacts with allylboronic acid in MeOH we could de-

velop a sequential one pot method including borylation of allylic alcohols

followed by allylation of 11i-j (Table 5) By applying this one pot procedure

for allylation the isolation step of allylboronic acids can be avoided The

optimized one pot procedure allowed us to synthesize homoallylic α-

hydroxy acids (12j-n) from α-keto acids (11i-j)

Table 5 Allylboration of α-keto acids with allylboronic acidsa

In situ generated boronic acid 10i reacted with pyruvic acid (11j) to af-

ford 12m with excellent diastereoselectivity (dr 982) (entry 4) The structure

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

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3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

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1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

31

of the compound 12m was confirmed by X-ray diffraction The allylboronic

acid formed from 8j is unstable and thus can not be isolated

However in situ generation of the allylboronic acid followed by the reac-

tion with 11j gives the homoallylic alcohol 12n with excellent selectivity

(entry 5)

42 Stereoselectivity of α-hydroxy acids

Ethyl pyruvate 11f (Table 4 entry 6) and pyruvic acid 11j (Table 5 entry

2) gave epimeric products 12f and 12k respectively (Scheme 32) This is

surprising as the two substrates 11f and 11j differ only by an ethyl group

Scheme 32 Different selectivity for the allylboration of pyruvic acid and its ester

derivative

We rationalized the different stereochemistries on the basis of different

steric and electronic interactions in the TS of the allylation (Figure 8) The

reaction with ester 11f proceeds via the expected Zimmerman-Traxler TS

(TS1) in which the bulky COOEt group is equatorial and the small Me

group is axial affording selectively the anti compound 12f However in TS2

the carboxyl group and the keto group form a chelate with the boron atom

The chelating geometry requires an axial COOH group and an equatorial Me

substituent Therefore the stereochemical outcome of the reaction would be

different and selectively forms the syn compound 12k

Figure 8 Proposed bicyclic transition state (TS2) for syn selectivity for α-hydroxy

acids (12j-n)

A similar chelation based syn selective allylation was reported by Kabal-

ka78

for allyl-Bpin with pyruvic acid 11j However in that reaction Et3N had

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

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34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

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39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

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93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

32

to be used for the allylation presumably for the deprotonation of pyruvic

acid

43 Conclusions for allylboration of carbonyl compounds

Allylboronic acids react with ketones without any additives to give

homoallylic alcohols These reactions can be conducted under mild condi-

tions typically at room temperature in dry aprotic solvents The reactions

proceed with a high level of chemo- regio- and diastereoselectivity In a

typical reaction the homoallylic alcohol is formed selectively with anti ste-

reochemistry Pyruvic acid and other α-keto acids react in MeOH with syn

stereoselectivity The synthesis of allylboronic acids and the allylation of α-

keto acids can be performed in a sequential one-pot reaction Since pyruvic

acid reacts with syn stereoselectivity while ethyl pyruvate reacts with anti

stereoselectivity a high level of stereocontrol can be achieved for these

types of ketones

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

1 The ACS Style Guide 3rd ed Oxford University Press New York 2006

2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

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5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

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82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

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85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

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88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

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94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

33

5 Synthesis of adjacent quaternary

stereocenters by catalytic asymmetric

allylboration of ketones (Paper IV)

Enantioselective synthesis of acyclic molecules with quaternary stereo-

centers is still a challenging task in organic synthesis79

Of course selective

formation of adjacent quaternary stereocenters is even more difficult Be-

cause of the bulky (non-hydrogen) substituents the steric repulsion between

the quaternary carbons results in a weak C-C -bond80

Such a -bond is

difficult to form and easy to cleave Relatively few methods are available for

the asymmetric single step creation of adjacent quaternary stereocenters25b

As mentioned in the introduction (Section 132) allyl boron reagents

have proven to be very useful for the creation of quaternary stereocenters In

addition in Chapter 4 we have shown that the allylation of ketones with

allylboronic acids is highly diastereoselective This gave the idea to develop

a new method for asymmetric allylboration of ketones using -disubstituted

allylboronic acids (such as 10f and 10g)

51 Method development for the asymmetric allylboration of ketones

We started to examine the BINOL based catalysts for our reactions since

these compounds have been found very efficient for allylboration methods

using allylborontes (see also Section 132)43-44 46

We screened various chi-

ral BINOL derivatives (Figure 9) It was found that compounds 4a-b and 4f

were the most efficient for the asymmetric allylboration (Table 6)

Figure 9 Chiral BINOL derivatives

34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

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34

We have found that the allylboration between 10f and ketone 11h in the

presence of 4a and tBuOH took place with high enantioselectivity (er 973)

and diastereoselectivity (dr gt982) When the enantiomer of 4a bromo-

BINOL 4f was used (entry 2) the opposite enantiomer of 13a was formed in

high selectivity (er 937) When these optimal conditions were changed the

enantioselectivity as well as in some cases the yield was depleted

Table 6 Asymmetric allylation conditions using chiral BINOL derivativesa

tBuOH was found to be a crucial additive to achieve a high enantiomeric

ratio under the above reaction conditions Replacing the tBuOH by other

tertiary alcohols (eg tAmOH 1-Adamantanol) leads a decrease of the selec-

tivity Interestingly the reaction did not proceed at all in the presence of

primary or secondary alcohols such as MeOH or iPrOH In the absence of

tertiary alcohol (entry 3) or molecular sieves (entry 4) the selectivity

dropped When both tBuOH and the molecular sieves were excluded (entry

5) the selectivity was somewhat higher (er 9010) than in the presence of

these additives I2-BINOL 4b was almost as efficient catalyst as its bromo

analogue 4a (cf entries 6 and 1) The parent BINOL 4d (entry 9) gave very

poor selectivity (er 5446) indicating the importance of the substituent in

BINOL for the enantioselectivity of the reaction BINOL derivative 4e with

the SMe substituent was more efficient than BINOL 4c (cf entries 7 and 8)

35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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65

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35

52 Stereocontrol in the asymmetric allylboration of ketone

We also examined the generality of the above asymmetric process by

synthesizing all four possible enantiomers of isomeric homoallylic alcohols

13a-d (Table 7) Gratifyingly applying the above optimal reaction condi-

tions we were able to synthesize all four stereoisomers with high enantiose-

lectivity As mentioned above (Table 6 entries 1-2) compound 10f reacted

with 11h in the presence of BINOL derivatives 4a and 4f affording the enan-

tiomeric pair 13a and 13b respectively (Table 7 entries 1-2) When the al-

lylation of 11h was conducted with nerylboronic acid 10g in the presence of

4b compound 13c (epimer of 13a) was formed (entry 3) with high enanti-

oselectivity

Table 7 Synthesis of four possible stereoisomers of 13aa

Finally we reacted nerylboronic acid 10g and the ketone 11h in the pres-

ence of 4f (entry 4) affording 13d (epimer of 13b) with a high selectivity

Accordingly using allylboronic acids 10f-g and enantiomeric BINOL deriv-

atives 4a-b and 4f a full control of the stereoselectivity can be achieved in

the asymmetric allylboration reaction of ketone 11h

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

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3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

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13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

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16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

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19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

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27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

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29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

36

53 Catalytic enantioselective allylboration of ketones

After studying the reactivity of allylboronic acids under various condi-

tions we decided to explore the scope of the reaction Using the above de-

scribed method we successfully synthesized several enantioenriched homoal-

lylic alcohols (Table 8) We found that changing the position of the bromo

substituent (11k) on the aromatic ring (entry 1) did not change the enantiose-

lectivity The reaction (entry 2) with methyl sulfonyl substituent in the ke-

tone component (11l) proceeded with very high enantioselectivity (er 973)

In addition the reaction was scaled up to five times and the selectivity of the

reaction did not drop The absolute configuration of 13f was determined by

X-ray diffraction (Figure 10) When we increased the size of the ketone

(entry 3) applying naphthyl derivative 11m the enantioselectivity was

slightly decreased (er 964) Heterocyclic ketone 11n was also subjected for

allylation (entry 4) affording 13h with high enantioselectivity and yield Not

only aromatic ketones but aliphatic ketone 11o can also be employed in the

selective allylboration (entry 5-6) For example cyclopropyl ketone 11o gave

13i with a er of 955 (entry 5) Using the R-Br2-BINOL derivative (4f) as

catalyst homoallylic alcohol 13j was formed selectively which is the other

enantiomer of 13i

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

1 The ACS Style Guide 3rd ed Oxford University Press New York 2006

2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

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88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

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94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

37

Table 8 Asymmetric allylation of ketones with γ-disubstituted allylboronic acidsa

Switching from geraniol boronic acid (10f) to nerylboronic acid (10g) the

diastereomeric alcohol derivatives 13k and 13l can be synthesized (entries 7-

8) In these reactions the process is faster and more selective when the iodo-

BINOL derivative 4b is used instead of the bromo-derivative 4a Not only

geranylboronic acid (10f) and nerylboronic acid 10g but also prenylboronic

acid 10k could be used for allylation The high enantioselectivity (er 955)

38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

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64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

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65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

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38

was also preserved in the prenylation reaction (entry 9) The homoprenyl

alcohol 13m can easily be synthesized from the reaction between 11l and

10k Absolute configuration of compound 13m was determined by X-ray

diffraction

Figure 10 Chem3D diagram of compound 13f from the X-ray diffraction data

54 Proposed mechanism for the enantioselectivity of the allylboration of ketones with allylboronic acids

We conducted experimental studies for exploration of the mechanism of

the enantioselectivity We hypothesized that the boronic acid (such as 10f)

may form the esterified species with the BINOL (4) before addition to the

ketones In order to get information on the nature of the interactions between

the allylboronic acids and the chiral BINOL ligand we monitored the mix-

ture of 10f and F2-BINOL 4c (Scheme 33) by 19

F NMR

Scheme 33 Reaction between geraniol boronic acid 10f and BINOL derivative 4c

The 19

F NMR of this reaction mixture (Figure 11b) showed two peaks

which are shifted downfield with respect to the 19

F NMR shift of the free

F2-BINOL 4c (Figure 11a) These changes of the 19

F NMR shifts suggest

that by mixing of 10f and 4c at least two new species are formed The first

one resonating at -1341 ppm is probably an associative complex (10f4c)

between 10f and 4c which is kept together by electrostatic forces andor

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

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3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

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78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

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37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

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40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

39

hydrogen bonds The second peak at -1307 ppm was tentatively assigned to

10l (Scheme 33) which is most likely the diester of 10f and 4c When mo-

lecular sieves (MS) 3Aring were added to this mixture the intensity of 10l was

considerably increased and the intensity of 10fhellip4c was decreased (Figure

11c)

Figure 11a-e

19F NMR spectra for the mixture of 4c and 10f under different condi-

tions

When iPrOH was added to the mixture of 10f 4c (in the presence of MS)

the signal for 10l was disappeared and the concentration of 10fhellip4c was

increased (Figure 11d) As mentioned in Section 51 iPrOH inhibits the

allylboration reaction probably because formation of the diester of the

allylboronic acid and the BINOL derivatives (such as 10l) was inhibited

Interestingly when tBuOH was added to the mixture of 10f 4c and MS

the concentration of 10l was decreased but it was still preserved in the reac-

tion mixture This is in line with our observation that addition of tBuOH did

not inhibit the reaction as the active species such as 10l is still available for

allylboration

Pellegrinet and co-workers81

have demonstrated that boronic acid diesters

of BINOL are more reactive than the corresponding monoesters Consider-

ing the high reactivity of BINOL diesters in allylboration and the expected

easy esterification of allylboronic acids and their anhydrides (see above) it

is reasonable to assume that BINOL diesters of allylboronic acids (such as

10l) are the active reaction intermediates in the above processes

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

1 The ACS Style Guide 3rd ed Oxford University Press New York 2006

2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

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62

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64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

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94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

40

541 Proposed models for enantioselectivity

Based on the above mechanistic studies and on the absolute configuration

of the products (13a-m) we provide a plausible mechanism in Figures 12-13

for the enantioselectivity of the above asymmetric reaction We suggest that

in the initial stage of the reaction the BINOL derivative (4a-b or 4f) and

boronic acid (10f-g10k) form the BINOL-boronate (Figures 12-13) The

allylboration is supposed to proceed via a Zimmerman-Traxler TSs 14a-d

The facial selectivity for a certain BINOL derivative is probably determined

by the steric effect of the bromo substituent of the BINOL and the methyl

group of the ketone For example In case of Si-face Si-face arrangement in

TS 14a (ketone in the front side allylboronate in back side) there is no steric

congestion between the bromine atom and the methyl group of the ketone

This TS provides the major enantiomer such as 13a In TS 14b (Figure 12)

when it is Re-face Re-face arrangement (ie the boronate is approaching at

the front side and the ketone is in the background) the steric repulsion be-

tween the bromine atom and the methyl group of the ketone may raise a high

activation barrier Since this TS is disfavored formation of 13b is sup-

pressed

Figure 12 Propose models for the enantioselectivity using the S-BINOL 4a

When the configuration of the BINOL is switched from S (such as 4a) to

R (such as 4f) the formation of 13b is favored via TS 14c which is in Re-

face Re-face arrangement (Figure 13) On the other hand formation of 13a is

disfavored via TS 14d (Figure 13) since there is a steric clash between the

bromine atom and the methyl group of the ketone in Si-face Si-face

arrangement

41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

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3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

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34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

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45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

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91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

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93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

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41

Figure 13 Propose models for the enantioselectivity considering the R-BINOL 4f

Similar type of transition states were also proposed by Chong and co-

workers for the asymmetric allylation of ketones using BINOL based

allylboronates43

542 Proposed catalytic cycle

Based on the above TS model (Figures 12-13) we propose a catalytic cy-

cle shown in Figure 14 which is exemplified with boronic acid 10f ketone

11h and BINOL derivative 4a

Figure 14 Proposed catalytic cycle for the asymmetric allylation of ketones

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

1 The ACS Style Guide 3rd ed Oxford University Press New York 2006

2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

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47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

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the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

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64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

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94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

42

As mentioned above we hypothesized that the reaction between al-

lylboronic acid 10f and BINOL derivative 4a leads to formation allylboronic

acid ester 10m This esterification process generates water which can be

adsorbed by the MS under the reaction conditions The active boronate spe-

cies 10m then undergoes allylation with ketone 11h to give 10n The enanti-

oselectivity is supposed to be determined in this addition step according to

the above proposed model (Figures 12-13) Catalyst 4a is captured in boric

acid ester 10n For regeneration of catalyst 4a this ester has to be hydro-

lyzed This hydrolysis may take place using water formed in the 4ararr10m

step On the other hand the solvolysis of 10n may also occur by tBuOH If

the free 4a is not available the non-asymmetric (self-catalyzed) allylboration

would take over thus decreasing the enantioselectivity of the process

55 Conclusions for the catalytic asymmetric allylboration

We have developed a catalytic enantioselective method to create adjacent

quaternary stereocenters in acyclic molecules from γ-disubstituted allyl

boronic acids and ketones in the presence of BINOL derivatives The reac-

tions proceeded under mild conditions affording enantioenriched homoal-

lylic alcohols A full control of the diastereo- and enantioselectivity can be

achieved in this process The process could be extended to various

allylboronic acids and ketones The mechanism of the enantioselectivity

could be rationalized on the basis of the Zimmer-Traxler model

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

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3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

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13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

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16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

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10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

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1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

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26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

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27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

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1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

43

6 Allylboration of imines indoles and

hydrazones (Paper V-VI)

Allylation of imines leads to stereodefined homoallylic amines which are

synthetic intermediates for instance in the total synthesis of alkaloids82

The

allylation of imines is usually considered to be more difficult than aldehydes

or ketones because of the low electrophilicity of the carbon atom in the

imine (C=N) compared to the carbonyl group (C=O)3a 83

In addition the

imineenamine tautomerization and EZ isomerization of imines may com-

plicate the outcome and the selectivity of the reaction As mentioned in Sec-

tion 133 many methods have been developed for the allylboration of imines

based on catalysis However relatively few examples are reported in the

literature for a successful reaction of allylboronic esters (such as allyl-Bpin)

and imines under external catalyst free conditions84

A diastereoselective

direct allylation of oximes with crotylboronates84b

was reported by

Hoffmann and co-workers (Scheme 34) Despite the harsh reaction condi-

tions (9 Kbar pressure) the stereoselectivity of this process is high

Scheme 34 Direct allylboration of oxime derivatives reported by Hoffmann and co-

workers

Considering the selective direct allylation of ketones with allylboronic

acids (Section 41) we decided to extend the synthetic scope of the reactions

to imines

61 Allylation of imines with allylboronic acids

We have found that allylboronic acids (10) readily react with imines (15)

typically at room temperature in dry DCM or CDCl3 without any additives

(Scheme 35) To ensure the dry conditions molecular sieves (4Aring) were add-

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

44

ed to the reaction mixture In the absence of molecular sieves (MS) the

imine substrates were hydrolyzed to aldehydes Then the aldehyde reacts

with allylboronic acid to form homoallylic alcohol instead of the desired

homoallylic amine product Interestingly the rate of hydrolysis of imines

(such as 15a) was higher in the presence of allylboronic acids 10 (and ab-

sence of molecular sieves) than in pure form (ie without 10)

Scheme 35 Allylation of imines with allylboronic acid

The allylboration of imines proceeds with very high regio- and stereose-

lectivity in most cases giving a single diastereomer as the final product

(Table 9) Cinnamyl boronic acid (10a) reacted readily at room temperature

with aryl and heteroaryl imines 15a-c to give homoallylic amines 16a-c as

single diastereomers (entries 1-3) The relative configuration of the com-

pound 16a was assigned on the basis of X-ray crystal structure (Figure 15)

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

1 The ACS Style Guide 3rd ed Oxford University Press New York 2006

2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

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128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

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45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

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53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

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60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

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73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

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1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

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78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

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82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

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94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

45

Table 9 Direct allylation of imines by allylboronic acidsa

Addition of octenylboronic acid (10d) to imine 15b was also proceeded

with high stereoselectivity (dr 955) to give 16d (entry 4) The reaction of

geranylboronic acid 10f with imine 15b was surprisingly fast and resulted in

16e (entry 5) bearing adjacent quaternary and tertiary stereocenters with a

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

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40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

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45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

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91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

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93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

46

diastereomeric ratio of 955 It is interesting to note that compound 10f has

been used by Li and co-workers85

for the synthesis of a homoallylamine-type

key intermediate in the total synthesis of hapalindole-Q

Figure 15 Chem3D diagram of compound 16a from the X-ray diffraction data

When compound 10a was added to the cyclic aldimine 15d (entry 6) an

interesting feature was observed for the stereochemistry This reaction yield-

ed the corresponding imine 16f as single diastereoisomer Surprisingly com-

pound 16f has also an anti-geometry which was confirmed by X-ray diffrac-

tion The same anti stereoselectivity for the allylation of both cyclic al-

dimine 15d (Z-geometry) and its acyclic counterpart 15a (E-geometry) was

unexpected The mechanistic aspects of the stereoselectivity of the allylbora-

tion of imines are further discussed in Section 64

Most of the ketimines such as the methyl analogs of 15a resisted to al-

lylboration under the above reaction conditions However cyclic ketimine

15e reacted with excellent stereoselectivity but much slower (in 24h) than

the aldimines (entry 7) This indicates that allylboronic acids are able to react

with ketimines as well but the reaction is sensitive to the steric factors The

reaction of 10a with imine 15e resulted in homoallylic pyrrolidine 16g with

adjacent quaternary and tertiary stereocenters as single diastereomer (entry

7) Glyoxylate imine 15f also reacted readily with 10a opening a new syn-

thetic route for stereoselective synthesis of -amino acid derivatives (entry

8) Compound 15g has both keto and aldimine functionalities (entry 9) but

only the imine functionality was transformed when 10a was added The

high chemoselectivity indicates that an aldimine reacts faster than a ketone

with an allylboronic acid Compound 16i might be useful to synthesis selec-

tive piperidine using ring closing metathesis (RCM)86

62 Allylation of indoles with allylboronic acids

After the successful allylation reaction of imines with allylboronic acids

our interest turned towards indole compounds Bubnov and co-workers re-

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

47

ported the allylboration of indoles by triallylborane87

The reaction required

harsh conditions but it proceeds with a high regio- and stereoselectivity In

addition Batey and co-workers88

recently showed that indoles react with

allyl-BF3K derivatives in the presence of Lewis acid such as BF3Et2O

We have found that allylboronic acids react readily with indoles 17a-c

without any additives under ambient conditions affording indolines The

reaction is highly regioselective for the C2 position of indoles as well as

stereoselective (Table 10)

Table 10 Regio- and stereoselective direct allylation of indolesa

Dichloromethane (DCM) proved to be the best solvent for the reactions

Polar protic solvent (eg MeOH) inhibits the reaction under our optimized

conditions Unlike imines indoles react cleanly with allylboronic acids even

in the absence of molecular sieves The allylboration with 10a completed in

a couple of hours using indoles 17a or 17b (entries 1 and 2) affording

indolines 18a-b with high yield and high stereoselectivity Aliphatic

allylboronic acid 10d also reacted smoothly with 17a to afford single regio-

and diastereomer 18c Geranylboronic acid 10f reacted with 17a creating

adjacent stereocenters (16d) including an all carbon quaternary stereocenter

This reaction is relatively slow probably because of the disubstitution at the

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

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28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

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11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

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39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

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2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

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91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

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94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

48

γ-position of 10f Despite a methyl substituent at the 2-position 17c was also

reacted (at 60 degC) with 10a affording 18e (entry 5)

63 Allylation of acyl hydrazones with allylboronic acids

N-Acylhydrazones have been widely used as stable imine equivalents to

synthesize homoallylic amine derivatives Kobayashi and co-workers89

reported that the allylation of acylhydrazones with allylsilanes proceeds with

syn selectivity Considering the above anti selective allylation of imines and

indoles using allylboronic acids (Section 61 and 62) we sought to develop

a syn selective allylation method for the synthesis of homoallylic amine

compounds Thus our attention turned towards allylboration of acylhydra-

zone compounds In a previous study Kobayashi and co-workers have

shown that allylboronates (such as allyl-Bpin reagents) react with N-

benzoylhydrazones in the presence of indium catalyst52

Considering the

high reactivity of the allylboronic acids for the allylation of ketones and

imines we hypothesized that these species may react with hydrazones with-

out external catalysts (such as indium) as well

Indeed we found that boronic acids (10) react with N-benzoylhydrazone

(19) under external catalyst free conditions with high regio- and stereoselec-

tivity (Table 11) DMSO was found to be the best solvent for the reaction

Conducting the reaction in THF MeOH or DCM at the same temperature as

in DMSO resulted in either low yield or no reaction The addition of cin-

namyl boronic acid 10a to the hydrazone 19a proceeded very smoothly at

room temperature affording single diastereomer 20a The relative stereo-

chemistry of the compound 20a was determined by X-ray diffraction The

X-ray structure of 20a clearly revealed that the allylation of hydrazones pro-

ceeds with a syn selectivity Heteroaromatic hydrazone 19b also reacted with

very high regio and stereoselectivity giving only a single diastereomeric

product

(entry 2) The selectivity and reactivity with aliphatic allylboronic acid 10d

was as high as with cinnamylboronic acid 10a when aromatic hydrazone

19a was used (entry 3)

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

1 The ACS Style Guide 3rd ed Oxford University Press New York 2006

2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

49

Table 11 Stereoselective direct allylation of N-acylhydrazonesa

As mentioned in Section 61 the reaction of aliphatic imines with

allylboronic acids (10) was problematic as allylboronic acids catalyze the

hydrolysis of aliphatic imines (Table 9) However alkyl hydrazones (such as

19c-e) are more stable to hydrolysis than the imine analogs Thus isopropyl

hydrazone 19c could easily be allylated with 10a affording syn product 20d

(entry 4) The stereochemistry of 20d was also determined by X-ray diffrac-

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

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2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

50

tion Reaction of aliphatic allylboronic acids with aliphatic imine derivatives

is particularly challenging These reactions could also be easily performed

(entry 5) but the stereoselectivity was dropped While most of the other

reactions afforded single diastereomer the allylation of aliphatic boronic

acid 10d with aliphatic hydrazone 19d afforded a mixture of diastereomers

in a ratio of 41 (entry 5) Keto-hydrazones have a more limited synthetic

scope than hydrazones derived from aldehydes Yet the hydrazone 19e was

successfully allylated by 10a affording 20f

As expected the stereoselectivity of the above allylation is dependent on

the geometry of the allylboronic acid Therefore geranylboronic acid 10f

reacted with excellent syn selectivity with 19a to give 20g On the other

hand nerylboronic acid 10g (stereoisomer of 10f) reacted with 19a with a

clean anti-selectivity affording 20h Both epimeric products 20g-h have two

contiguous stereocenters including one all carbon quaternary stereocenter

64 Mechanistic study and proposal for the allylation of aldimines

The most intriguing mechanistic aspect of the above allylboration of E

and Z imines is the fast anti-selective allylation (Table 9) Since the stereo-

chemistry is the same as for allylboration of aldehydes and ketones we

hypothesized that the reaction with imines also takes place according to the

ZT model (Scheme 36) via a chair-type TS (see also Section 13) According

to the ZT model (Scheme 36) syn-selectivity is expected for the reaction of

an E-allylboronate and an E-imine However the above reactions (Table 9)

using E-allylboronic acids with acyclic E-imines are anti-selective In addi-

tion the allylboration of Z-allylboronic acids and Z-imines (such as 15d

Table 9 entry 6) also proceeds with anti-selectivity This suggests that acy-

clic E-imines undergo isomerization prior to the allylation process

Scheme 36 Expected syn selectivity from E-imine following ZT model

The thermal isomerization of aldimines has a high activation energy90

For example according to the 1H NMR spectrum of 15a it exists as a stable

E isomer in CDCl3 even at elevated temperature (50 degC) Recently Piers and

co-workers91

have reported that boron-based Lewis acids such as B(C6F5)3

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

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2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

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27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

51

are able to facilitate the isomerization of aldimines Therefore we hypothe-

sized that allylboronic acids or allylboroxines may catalyze the EZ isomeri-

zation of imines prior to the allylation Since allylboronic acid 10a allylates

E-aldimine (15a) rapidly we studied the EZ isomerization of 15a in the

presence of aryl boroxine 21a (Scheme 37) which does not undergo C-C

bond formation reaction with imines Boroxine 21a was prepared from the

corresponding arylboronic acid (4-fluorophenyl boronic acid) When E-

imine 15a and boron compound 21a were mixed in CDCl3 at room tempera-

ture (Scheme 37) a new species 22a was formed In 22a the methyl and the

phenyl groups are in Z-configuration along the C=N bond which was con-

firmed by NOE experiments

Scheme 37 EZ isomerization of 13a in the presence of aryl boroxine (Ar = 4-

fluorophenyl) The significant 1H NOEs are shown

The Z relationship (syn geometry) of the N-methyl and phenyl groups in

22a satisfactorily explains the anti-selectivity of the allylboration via a chair

TS in line with the ZT model To further confirm this hypothesis DFT mod-

eling studies were performed to rationalize the stereoselectivity of the allyla-

tion of imines The results show (Figure 16) that the formation of imine-

boroxine complex 22c from 15aprime (Z-imine) and allyl boroxine 21b is an ex-

ergonic process (by -41 kcal mol-1

) This assumes that facile EZ isomeriza-

tion of the imine takes place as established above for 15a (Scheme 37) It is

noteworthy that 22c in which the N-methyl and phenyl groups are in Z-

geometry is more stable by 62 kcal mol-1

than 22b which has an E-

geometry Thus the order of stability is opposite for the boroxine coordinat-

ed (22b vs 22c) and for the free imines (15a vs 15aprime)

From 22c the allylboration proceeds via chair TS 23a with a low activa-

tion barrier (149 kcal mol-1

) affording 24a with anti-selectivity This is in

agreement with the ZT model The chair conformation of TS structure 23a

and the TS geometry of allylboration of aldehydes32b 35 92

are very similar

which is in line with the identical stereochemistry observed for the two pro-

cesses Allylation of the other imine-allyl boroxine complex (22b) or 15a in

which the N-methyl and phenyl are in E geometry requires 54 kcal mol-1

higher activation barriers to give the syn product 24b The high barrier is

apparently because of the axial position of the phenyl group in 23b which is

sterically unfavorable in line with the ZT model (Scheme 36) We have also

calculated the activation barriers via boat TSs84b

However formation of the

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

1 The ACS Style Guide 3rd ed Oxford University Press New York 2006

2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

52

anti product 24a via boat TS involves a much higher barrier than itrsquos chair

TS 23a (by 780 kcal mol-1

) which is mainly because of unfavorable eclips-

ing strains and 14-diaxial strain in the boat form These are well known by

the analysis of the conformational energy surface of cyclohexane93

Figure 16 Reaction profile for the allylboration of 15a in the presence of allylbor-

oxine 21b The ΔG values are given in kcal mol-1

65 Proposed mechanism for the allylboration of hydrazones

Although the allylation of imines with allylboronic acids is anti selective

the allylation of hydrazones is syn selective Aldimine 15a and its analog

compound benzoylhydrazone 19a reacted with allylboronic acid 10a under

very similar conditions affording epimeric compounds 16a and 20a (Scheme

38)

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

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3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

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10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

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14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

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20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

53

Scheme 38 Allylation of 15a and 19a with cinnmyl boronic acid 10a

As we have shown imine 15a undergoes E to Z isomerization prior to the

allylation and it reacts with anti selectivity with 10a (Figure 16) The E to Z

isomerization of 15a was even catalyzed by arylboronic acid derivatives

Conversely our studies indicate that under similar reaction conditions 19a

did not undergo E to Z isomerization

Scheme 39 Plausible mechanism for allylboration of hydrazones

Thus 19a undergoes the addition to allylboronic acid (such as 10a) with

an E-geometry However this would lead to unfavorable 13-diaxial repul-

sions involving the phenyl group of 19a in the Zimmerman-Traxler TS (27)

of the reaction (Scheme 39) This thermodynamically unfavorable diaxial

interaction can probably be compensated by chelation of the nitrogen and

oxygen atoms of the hydrazone functional group to the B(OH)2 group such

as in 25a The chelation can be reinforced by water elimination to give 26

The water elimination requires the presence of a proton on one of the nitro-

gen atoms of 19a When this hydrogen is replaced by a methyl group the

allylation reaction cannot be performed The allylation via transition state 27

leads to syn selectivity affording the compound 20a The syn selectivity in

allylation of hydrazones using allylchlorosilanes was also explained by a

similar chelation control89 94

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

1 The ACS Style Guide 3rd ed Oxford University Press New York 2006

2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

54

66 Proposed mechanism for the allylboration of indoles

As mentioned before (Section 62) the allylation of indoles by

allylboronic acids proceeds with anti selectivity under additive free condi-

tions The anti selectivity was also observed for the allylation of ketones and

imines with allylboronic acids and a Zimmerman-Traxler (ZT) model was

used to describe the obtained selectivity We also hypothesized that the anti

selective allylation of indole proceeds via a ZT transition state (Scheme 40)

The first step is supposed to be the coordination between the boronic acid

10a and the indole 17a to form an adduct 28a As mentioned above Bubnov

and co-workers reported allylation of indoles using triallylborane reagents87a

According to the mechanistic studies of these authors a [13] proton shift

was observed in indole prior to allylation We also propose a similar proton

shift in indole which leads to form 28b from 28a In fact 28b can be regard-

ed as a complex of allylboronic acid and a cyclic imine Subsequently 28b

may undergo allylboration via ZT TS 28bprime to give 18a Accordingly the

same principles determine the stereochemistry of the allylation for indoles

(Scheme 40) and imines (Figure 16) A similar mechanism was also

proposed by Batey and co-workers88

for the allylation of indoles using potas-

sium trifluoroborate salts and BF3Et2O

Scheme 40 Proposed mechanism for the allylation of indoles with allylboronic acid

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

1 The ACS Style Guide 3rd ed Oxford University Press New York 2006

2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

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45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

55

67 Conclusions for the allylboration of imines indoles and hydrazones

Allylboronic acids readily react with imines indoles and hydrazones

under mild conditions This transformation can be employed to synthesize a

wide range of diastereoenriched homoallylic amines The allylation proceeds

with very high anti stereoselectivity for both E and Z imines and indoles

The experimental and theoretical studies show that boroxines catalyze the E

to Z isomerization of acyclic aldimines prior to allylation Unlike for imines

a syn selective allylation was observed for acylhydrazones Our experiments

showed that the EZ isomerization does not occur for the hydrazones in the

presence of boroxines A chelation controlled bicyclic transition state was

proposed to rationalize the syn selectivity of the allylboration of hydrazones

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

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61

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12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

56

7 Concluding remarks

We developed palladium-catalyzed selective allylic CminusH and CminusOH

functionalization methods These catalytic procedures allowed us to synthe-

size allylic trifluoroacetates and allylboronic acids with high regio- and

stereoselectivity

Palladium catalyzed CminusH trifluoroacetoxylation can be carried out using

PIFA as oxidant and trifluoroacetate source The method is suitable for the

synthesis of allylic trifluoroacetaes from both cyclic and acyclic alkenes The

trifluoroacetoxylation of monosubstituted cyclic alkenes proceeds with high

regio- and stereoselectivity The reaction is suggested to proceed via a

Pd(II)Pd(IV) catalytic cycle

A new process was developed for the synthesis and isolation of

allylboronic acids Allylboronic acids easily form boroxines which are very

oxygen sensitive species Therefore the purification and isolation of

allylboronic acids have been done under inert conditions

Allylboronic acids readily react with ketones and imines at room temper-

ature without additives The reaction proceeds with remarkably high stere-

oselectivity The procedure is suitable for selective synthesis of homoallylic

alcohols and amines with contiguous stereocenters The reactions for imines

proceed with anti stereoselectivity We have found that allylboroxines

catalyze the isomerization of acyclic imines prior to the allylation which

explains the observed stereoselectivity

We have successfully developed a catalytic asymmetric allylboration

process for ketones using allylboronic acids in the presence of BINOL deriv-

atives The method can be used for the synthesis of homoallylic alcohols

with two adjacent quaternary carbon stereocenters A high level of control

of the enantioselectivity can be achieved by varying the allylboronic acid

substrates and the BINOL catalyst

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

57

8 Acknowledgements

I would like to express my sincere gratitude to the following people

My research supervisor Professor Kaacutelmaacuten J Szaboacute for accepting me as a

PhD candidate in his group I am grateful to you for your inspiration sugges-

tions ideas and discussions throughout these past years Tack foumlr allt

Professor Pher G Andersson for showing interest in this thesis

My co-authors Professor Fahmi Himo Professor Lars Eriksson Dr Lukasz

T Pilarski Dr Mihai Raducan Dr Arindam Das Dr Genping Huang

Tobias Vollgraff and Elias Pershagen for excellent collaboration

Sebastian Kaminski and Nuacuteria Miralles Prat for being delightful co-workers

in the lab

Dr Colin Diner Dr Weiming Yuan Dr Marie Charlotte Belhomme Dr

Antonio Bermejo Goacutemez Nadia Ilchenko providing valuable suggestions to

improve this thesis

Dr Johanna Larsson Dr Nicklas Selander Dr Lukasz T Pilarski Dr

Mihai Raducan Tobias Vollgraff Stalin Reddy Pathipati Dr Tony Zhao

Angela Van der Werf and Kilian Colas for all the assistance and thoughtful

discussions inside and outside of the lab

Past and present members of the Szaboacute group My Chinese teachers Dong

Wang and Weiming Yuan 谢谢

Dr Robert Pendrill and Dr Carolina Fontana for their kind assistance to

perform NOE experiments Cristiana Margarita for helping in SFC

All the lecturers I had in different courses at this department

The TA Staff and all the other employees in the department for helping in

many issues

Ahsan Habib for his continuous inspiration and wishes My Friends and family especially my beloved parents for their best support

in my life To my wife Najnin for her best effort to make our time enjoyable

Aringngpannefoumlreningens Forskningsstiftelse Stiftelsen Sigurd och Elsa Goljes

Minne C F Liljevalchs Jors Knut och Alice Wallenbergs Kungliga

Vetenskapsakademien Sture ErikssonsCarl Tryggers Stiftelse Wenner-

Gren Foundation for travel grant and research fund

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

1 The ACS Style Guide 3rd ed Oxford University Press New York 2006

2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

58

9 Summary in Swedish

Denna avhandling fokuserar paring tvaring huvudomraringden inom organisk syntes

palladiumkatalyserad funktionalisering av alkener och allylalkoholer samt

utveckling av nya allylborerings-reaktioner

Vi har utvecklat en selektiv palladiumkatalyserad allylisk

trifluoroacetoxylerings-reaktion baserad paring CminusH funktionalisering Allyliska

trifluoracetater syntetiserades fraringn funktionaliserade olefiner under oxidativa

betingelser Reaktionerna sker under milda betingelser med en houmlg grad av

diastereoselektivitet Mekanistiska studier av den allyliska CminusH

trifluoroacetoxyleringen indikerar att reaktionen fortskrider via en (η3-allyl)

palladium (IV) intermediaumlr

En palladiumkatalyserad regio- och stereoselektiv syntes av allylborsyror

fraringn allylalkoholer har utvecklats Diborsyra B2(OH)4 anvaumlndes som borkaumllla

i denna process

Reaktiviteten av allylborsyrorna studerades i tre typer av allylborerings-

reaktioner allylborering av ketoner iminer och acyl-hydrazoner Alla tre

processer utfoumlrdes under milda betingelser utan tillsatser Reaktionerna sker

med anmaumlrkningsvaumlrt houmlg regio- och stereoselektivitet

En asymmetrisk allylborering av ketoner utvecklades ocksaring I denna

process anvaumlndes kirala BINOL-derivat som katalysatorer Reaktionen

mellan γ-disubstituerade allylborsyror och olika aromatiska och alifatiska

ketoner gav homoallyliska alkoholer med angraumlnsande kvartenaumlra centra

med utmaumlrkt regio- stereo- och enantioselektivitet (upp till 973 er) i houmlgt

utbyte Selektiviteten i allylborerings-reaktionerna kan rationaliseras med

hjaumllp av Zimmerman-Traxler TS-modellen

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

11 References

1 The ACS Style Guide 3rd ed Oxford University Press New York 2006

2 (a) Tsuji J In Palladium Reagents and Catalysts New Perspectives for the 21st Century John Wiley amp Sons Ltd Chichester 2004 (b) Selander N J Szaboacute K Chem Rev 2010 111 2048-2076 (c) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169 (d) Engle K M Mei T-S Wasa M Yu J-Q Acc Chem Res 2012 45 788-802 (e) McDonald R I Liu G Stahl S S Chem Rev 2011 111 2981-3019

3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

59

10 Appendix A

Articles are reprinted with the permission from the following publishers

I Alam R Pilarski L T Pershagen E Szaboacute K J J Am Chem

Soc 2012 134 8778ndash8781

Copyright copy 2012 American Chemical Society

II Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51

13050ndash13053

Copyright copy 2012 Wiely-VCH Verlag GmbH amp Co KGaA Wein-

heim

III Alam R Raducan M Eriksson L Szaboacute K J Org Lett 2013 15

2546ndash2549

Copyright copy 2013 American Chemical Society

IV Alam R Vollgraff T Eriksson L Szaboacute K J J Am Chem Soc

2015 137 11262-11265

Copyright copy 2015 American Chemical Society

V Alam R Das A Huang G Himo F Eriksson L Szaboacute K J

Chem Sci 2014 5 2732ndash2738

Copyright copy The Royal Society of Chemistry 2014

VI Das A Alam R Eriksson L Szaboacute K J Org Lett 2014 16

3808ndash3811

Copyright copy 2014 American Chemical Society

60

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3 (a) Hall D G Boronic Acids Preparation and Applications in Organic Synthesis Medicine and Materials Wiley-VCH Verlag amp Co KGaA Weinheim 2011 (b) Lachance H Hall D G Allylboration of Carbonyl Compounds John Wiley amp Sons Inc 2012 (c) Erick M Carreira L K Classics in Stereoselective Synthesis WILEY-VCH Verlag GmbH amp Co KGaA 2009

4 (a) Heumann A Palladium-Catalyzed Allylic Substitutions In Transition Metals for Organic Synthesis Wiley-VCH Verlag GmbH 2008 pp 307-320 (b) Tsuji J The TsujindashTrost Reaction and Related CarbonndashCarbon Bond Formation Reactions Overview of the PalladiumndashCatalyzed CarbonndashCarbon Bond Formation via π-Allylpalladium and Propargylpalladium Intermediates In Handbook of Organopalladium Chemistry for Organic Synthesis John Wiley amp Sons Inc 2003 pp 1669-1687 (c) Trost B M Van Vranken D L Chem Rev 1996 96 395-422

5 Liron F Oble J Lorion M M Poli G Eur J Org Chem 2014 2014 5863-5883

6 McMurry J E Kocovsky P Tetrahedron Lett 1984 25 4187-90 7 (a) Hansson S Heumann A Rein T Aringkermark B J Org Chem

1990 55 975-984 (b) Aringkermark B Larsson E M Oslob J D J Org Chem 1994 59 5729-5733 (c) Heumann A Aringkermark B Angew Chem Int Ed 1984 23 453-454

8 Grennberg H Simon V Baumlckvall J-E J Chem Soc Chem Commun 1994 265-266

9 (a) Chen M S White M C J Am Chem Soc 2004 126 1346-1347 (b) Chen M S Prabagaran N Labenz N A White M C J Am Chem Soc 2005 127 6970-6971

10 (a) Campbell A N White P B Guzei I A Stahl S S J Am Chem Soc 2010 132 15116-15119 (b) Diao T Stahl S S Polyhedron 2014 84 96-102

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

60

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12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

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14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

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1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

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26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

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27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

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30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

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78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

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46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

61

11 (a) Check C T Henderson W H Wray B C Vanden Eynden M J Stambuli J P J Am Chem Soc 2011 133 18503-18505 (b) Pilarski L T Selander N Boumlse D Szaboacute K J Org Lett 2009 11 5518-5521

12 (a) Duumlfert M A Billingsley K L Buchwald S L J Am Chem Soc 2013 (b) Duong H A Huleatt P B Tan Q-W Shuying E L Org Lett 2013 15 4034-4037 (c) Deng H-P Wang D Szaboacute K J J Org Chem 2015 80 3343-3348

13 (a) Brown H C Racherla U S Pellechia P J J Org Chem 1990 55 1868-1874 (b) Roush W R Walts A E Hoong L K J Am Chem Soc 1985 107 8186-8190 (c) Roush W R Ando K Powers D B Palkowitz A D Halterman R L J Am Chem Soc 1990 112 6339-6348

14 Ishiyama T Ahiko T-a Miyaura N Tetrahedron Lett 1996 37 6889-6892

15 (a) Olsson V J Sebelius S Selander N Szaboacute K J J Am Chem Soc 2006 128 4588-4589 (b) Selander N Kipke A Sebelius S Szaboacute K J J Am Chem Soc 2007 129 13723-13731 (c) Selander N Szabo K J Chem Commun 2008 3420-3422 (d) Dutheuil G Selander N Szaboacute K J Aggarwal V K Synthesis 2008 14 2293-2297

16 Larsson J M Szaboacute K J J Am Chem Soc 2013 135 443-455 17 (a) Selander N Willy B Szaboacute K J Angew Chem Int Ed 2010

49 4051-4053 (b) Deng H-P Eriksson L Szabo K J Chem Commun 2014 50 9207-9210

18 (a) Ito H Miya T Sawamura M Tetrahedron 2012 68 3423-3427 (b) Ito H Kawakami C Sawamura M J Am Chem Soc 2005 127 16034-16035

19 Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857

20 Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 21 Guzman-Martinez A Hoveyda A H J Am Chem Soc 2010 132

10634-10637 22 Park J K Lackey H H Ondrusek B A McQuade D T J Am

Chem Soc 2011 133 2410-2413 23 Zhang P Roundtree I A Morken J P Org Lett 2012 14 1416-

1419 24 (a) Pelz N F Woodward A R Burks H E Sieber J D Morken

J P J Am Chem Soc 2004 126 16328-16329 (b) Kliman L T Mlynarski S N Ferris G E Morken J P Angew Chem Int Ed 2012 51 521-524

25 (a) Althaus M Mahmood A Suaacuterez J R Thomas S P Aggarwal V K J Am Chem Soc 2010 132 4025-4028 (b) Chen J L Y Aggarwal V K Angew Chem Int Ed 2014 53 10992-10996

26 (a) Chemler S R Roush W R Recent Applications of the Allylation Reaction to the Synthesis of Natural Products In Modern

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

62

Carbonyl Chemistry Wiley-VCH Verlag GmbH 2007 pp 403-490 (b) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2013 113 5595-5698 (c) Yus M Gonzaacutelez-Goacutemez J C Foubelo F Chem Rev 2011 111 7774-7854

27 Mikhailov B M Bubnov Y N Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya 1964 1874-1878

28 (a) Hoffmann R W Zeiss H J J Org Chem 1981 46 1309-1314 (b) Hoffmann R W Zeiss H-J Angew Chem Int Ed 1979 18 306-307

29 (a) Jadhav P K Bhat K S Perumal P T Brown H C J Org Chem 1986 51 432-439 (b) Chen G-M Ramachandran P V Brown H C Angew Chem Int Ed 1999 38 825-826

30 Chen M Roush W R Org Lett 2010 12 2706-2709 31 Zimmerman H E Traxler M D J Am Chem Soc 1957 79 1920-

1923 32 (a) Hoffmann R W Angew Chem Int Ed 1982 21 555-566 (b)

Li Y Houk K N J Am Chem Soc 1989 111 1236-1240 33 (a) Kennedy J W J Hall D G J Am Chem Soc 2002 124

11586-11587 (b) Kennedy J W J Hall D G Angew Chem Int Ed 2003 42 4732-4739 (c) Ishiyama T Ahiko T-a Miyaura N J Am Chem Soc 2002 124 12414-12415

34 Sakata K Fujimoto H J Am Chem Soc 2008 130 12519-12526 35 Wang H Jain P Antilla J C Houk K N J Org Chem 2013

78 1208-1215 36 (a) Schneider U Kobayashi S Angew Chem Int Ed 2007 46

5909-5912 (b) Schneider U Ueno M Kobayashi S J Am Chem Soc 2008 130 13824-13825 (c) Shibasaki M Kanai M Chem Rev 2008 108 2853-2873 (d) Yamaguchi M Morita N Schneider U Kobayashi S Adv Synth Catal 2010 352 1461-1465

37 Roush W R Adam M A Walts A E Harris D J J Am Chem Soc 1986 108 3422-3434

38 (a) Burgos C H Canales E Matos K Soderquist J A J Am Chem Soc 2005 127 8044-8049 (b) Canales E Prasad K G Soderquist J A J Am Chem Soc 2005 127 11572-11573

39 Fernaacutendez E Pietruszka J Frey W J Org Chem 2010 75 5580-5589

40 Ding J Hall D G Angew Chem Int Ed 2013 52 8069-8073 41 Chen J L Y Scott H K Hesse M J Willis C L Aggarwal V

K J Am Chem Soc 2013 135 5316-5319 42 (a) Rauniyar V Hall D G Angew Chem Int Ed 2006 45 2426-

2428 (b) Rauniyar V Zhai H Hall D G J Am Chem Soc 2008 130 8481-8490

43 Wu T R Shen L Chong J M Org Lett 2004 6 2701-2704 44 (a) Lou S Moquist P N Schaus S E J Am Chem Soc 2006

128 12660-12661 (b) Barnett D S Moquist P N Schaus S E Angew Chem Int Ed 2009 48 8679-8682

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

63

45 Wada R Oisaki K Kanai M Shibasaki M J Am Chem Soc 2004 126 8910-8911

46 Zhang Y Li N Qu B Ma S Lee H Gonnella N C Gao J Li W Tan Z Reeves J T Wang J Lorenz J C Li G Reeves D C Premasiri A Grinberg N Haddad N Lu B Z Song J J Senanayake C H Org Lett 2013 15 1710-1713

47 (a) Ramadhar T R Batey R A Synthesis 2011 2011 1321-1346 (b) Cui Y Li W Sato T Yamashita Y Kobayashi S Adv Synth Catal 2013 355 1193-1205

48 Yamamoto Y Asao N Chem Rev 1993 93 2207-2293 49 Li S-W Batey R A Chem Commun 2004 1382-1383 50 Sugiura M Hirano K Kobayashi S J Am Chem Soc 2004 126

7182-7183 51 (a) Wu T R Chong J M J Am Chem Soc 2006 128 9646-9647

(b) Lou S Moquist P N Schaus S E J Am Chem Soc 2007 129 15398-15404 (c) Canales E Hernandez E Soderquist J A J Am Chem Soc 2006 128 8712-8713

52 (a) Schneider U Chen I H Kobayashi S Org Lett 2008 10 737-740 (b) Kobayashi S Konishi H Schneider U Chem Commun 2008 2313-2315

53 (a) Giri R Shi B-F Engle K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (b) Chen X Engle K M Wang D-H Yu J-Q Angew Chem Int Ed 2009 48 5094-5115 (c) Sandtorv A H Adv Synth Catal 2015 357 2403-2435 (d) Labinger J A Bercaw J E Nature 2002 417 507-514

54 (a) Bruumlckl T Baxter R D Ishihara Y Baran P S Acc Chem Res 2012 45 826-839 (b) Yamaguchi J Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009

55 Campbell A N Stahl S S Acc Chem Res 2012 45 851-863 56 (a) Tsuji J Palladium Reagents and Catalysts New Perspectives for

the 21st Century John Wiley amp Sons Chichester 2004 (b) Franzeacuten J Loumlfstedt J Falk J Baumlckvall J-E J Am Chem Soc 2003 125 14140-14148

57 Stang E M White M C Angew Chem Int Ed 2011 50 2094-2097

58 Gormisky P E White M C J Am Chem Soc 2011 133 12584-12589

59 (a) Mazuela J Banerjee D Baumlckvall J-E J Am Chem Soc 2015 137 9559-9562 (b) Deng Y Baumlckvall J-E Angew Chem Int Ed 2013 52 3217-3221 (c) Loumlfstedt J Franzeacuten J Baumlckvall J-E J Org Chem 2001 66 8015-8025

60 (a) Tsuji Y Funato M Ozawa M Ogiyama H Kajita S Kawamura T J Org Chem 1996 61 5779-5787 (b) Zhao T S N Szaboacute K J Org Lett 2012 14 3966-3969 (c) Obora Y Ogawa Y Imai Y Kawamura T Tsuji Y J Am Chem Soc 2001 123 10489-10493

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

64

61 Henderson W H Check C T Proust N Stambuli J P Org Lett 2010 12 824-827

62 (a) Trost B M Metzner P J J Am Chem Soc 1980 102 3572-3577 (b) Trost B M Weber L Strege P E Fullerton T J Dietsche T J J Am Chem Soc 1978 100 3416-3426

63 Kurosawa H Ogoshi S Kawasaki Y Murai S Miyoshi M Ikeda I J Am Chem Soc 1990 112 2813-2814

64 Sebelius S Olsson V J Szaboacute K J J Am Chem Soc 2005 127 10478-10479

65 Baber R A Norman N C Orpen A G Rossi J New J Chem 2003 27 773-775

66 (a) Selander N Sebelius S Estay C Szaboacute K J Eur J Org Chem 2006 4085-4087 (b) Molander G A Trice S L J Kennedy S M Dreher S D Tudge M T J Am Chem Soc 2012 134 11667-11673 (c) Molander G A Trice S L J Dreher S D J Am Chem Soc 2010 132 17701-17703 (d) Molander G A Trice S L J Kennedy S M J Org Chem 2012 77 8678-8688

67 Pilarski L T Szaboacute K J Angew Chem Int Ed 2011 50 8230-8232

68 McCloskey A L Brotherton R J Boone J L J Am Chem Soc 1961 83 4750-4754

69 Raducan M Alam R Szaboacute K J Angew Chem Int Ed 2012 51 13050-13053

70 Simonov P A Troitskii S Y Likholobov V A Kinet Catal 2000 41 255-269

71 (a) Korich A L Iovine P M Dalton Transactions 2010 39 1423-1431 (b) Snyder H R Kuck J A Johnson J R J Am Chem Soc 1938 60 105-111

72 Selander N Paasch J R Szaboacute K J J Am Chem Soc 2010 133 409-411

73 Hoffmann R W Sander T Chemische Berichte 1990 123 145-152

74 Kraus G A Shimagaki M Tetrahedron Lett 1981 22 1171-1174 75 Debleds O Campagne J-M J Am Chem Soc 2008 130 1562-

1563 76 Dunet G Mayer P Knochel P Org Lett 2008 10 117-120 77 (a) Dutta B Gilboa N Marek I J Am Chem Soc 2010 132

5588-5589 (b) Mejuch T Dutta B Botoshansky M Marek I Org Biomol Chem 2012 10 5803-5806 (c) Takeda T Yamamoto M Yoshida S Tsubouchi A Angew Chem Int Ed 2012 51 7263-7266

78 Wang Z Meng X-J Kabalka G W Tetrahedron Lett 1991 32 1945-1948

79 (a) Quasdorf K W Overman L E Nature 2014 516 181-191 (b) Leonori D Aggarwal V K Acc Chem Res 2014 47 3174-3183 (c) Marek I Minko Y Pasco M Mejuch T Gilboa N Chechik H Das J P J Am Chem Soc 2014 136 2682-2694

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

92 (a) Omoto K Fujimoto H J Org Chem 1998 63 8331-8336 (b) Hesse M J Essafi S Watson C G Harvey J N Hirst D Willis C L Aggarwal V K Angew Chem Int Ed 2014 53 6145-6149

93 (a) Cremer D Szaboacute K J Ab Initio Studies of Six-Membered Rings Present Status and Future Developments In Conformational Behavior of Six-Membered Rings Analysis Dynamics and Stereoelectronic Effects VCH 1995 p 59 (b) Anslyn E V Dougherty D A Modern Physical Organic Chemistry University Science Books 2006 p 107

94 Berger R Duff K Leighton J L J Am Chem Soc 2004 126 5686-5687

65

80 Gonthier J F Wodrich M D Steinmann S N Corminboeuf C Org Lett 2010 12 3070-3073

81 Paton R S Goodman J M Pellegrinet S C Org Lett 2009 11 37-40

82 (a) Kobayashi S Ishitani H Chem Rev 1999 99 1069-1094 (b) Bloch R Chem Rev 1998 98 1407-1438

83 Nugent T C Chiral Amine Synthesis Methods Developments and Applications WILEY-VCH Verlag GmbH amp Co KGaA Weinheim 2010 p 2

84 (a) Hoffmann R W Eichler G Endesfelder A Liebigs Ann Chem 1983 1983 2000-2007 (b) Hoffmann R W Endesfelder A Liebigs Ann Chem 1987 215-219 (c) Wuts P G M Jung Y W J Org Chem 1991 56 365-372

85 Lu Z Yang M Chen P Xiong X Li A Angew Chem Int Ed 2014 53 13840-13844

86 Piao F Mishra M K Jang D O Tetrahedron 2012 68 7050-7055

87 (a) Bubnov Yury N Zhun Ilya V Klimkina Elena V Ignatenko Anatoly V Starikova Zoya A Eur J Org Chem 2000 3323-3327 (b) Kuznetsov N Y Khrustalev V N Godovikov I A Bubnov Y N Eur J Org Chem 2006 113-120

88 Nowrouzi F Batey R A Angew Chem Int Ed 2013 52 892-895 89 (a) Kobayashi S Hirabayashi R J Am Chem Soc 1999 121

6942-6943 (b) Hirabayashi R Ogawa C Sugiura M Kobayashi S J Am Chem Soc 2001 123 9493-9499

90 Curtin D Y Grubbs E J McCarty C G J Am Chem Soc 1966 88 2775-2786

91 Blackwell J M Piers W E Parvez M McDonald R Organometallics 2002 21 1400-1407

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